Substituted oxopyridine derivatives and use thereof in the treatment of cardiovascular disorders

ABSTRACT

The invention relates to substituted oxopyridine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and oedemas, and also ophthalmic disorders.

The invention relates to substituted oxopyridine derivatives and toprocesses for their preparation, and also to their use for preparingmedicaments for the treatment and/or prophylaxis of diseases, inparticular cardiovascular disorders, preferably thrombotic orthromboembolic disorders, and oedemas, and also ophthalmic disorders.

Blood coagulation is a protective mechanism of the organism which helpsto “seal” defects in the wall of the blood vessels quickly and reliably.Thus, loss of blood can be avoided or kept to a minimum. Haemostasisafter injury of the blood vessels is effected mainly by the coagulationsystem in which an enzymatic cascade of complex reactions of plasmaproteins is triggered. Numerous blood coagulation factors are involvedin this process, each of which factors converts, on activation, therespectively next inactive precursor into its active form. At the end ofthe cascade comes the conversion of soluble fibrinogen into insolublefibrin, resulting in the formation of a blood clot. In bloodcoagulation, traditionally the intrinsic and the extrinsic system, whichend in a final joint reaction path, are distinguished. Here, factors Xaand IIa (thrombin) play key roles: Factor Xa bundles the signals of thetwo coagulation paths since it is formed both via factor VIIa/tissuefactor (extrinsic path) and via the tenase complex (intrinsic path) byconversion of factor X. The activated serine protease Xa cleavesprothrombin to thrombin which, via a series of reactions, transduces theimpulses from the cascade to the coagulation state of the blood.

In the more recent past, the traditional theory of two separate regionsof the coagulation cascade (extrinsic and intrinsic path) has beenmodified owing to new findings: In these models, coagulation isinitiated by binding of activated factor VIIa to tissue factor (TF). Theresulting complex activates factor X, which in turn leads to generationof thrombin with subsequent production of fibrin and platelet activation(via PAR-1) as injury-sealing end products of haemostasis. Compared tothe subsequent amplification/propagation phase, the thrombin productionrate is low and as a result of the occurrence of TFPI as inhibitor ofthe TF-FVIIa-FX complex is limited in time.

A central component of the transition from initiation to amplificationand propagation of coagulation is factor XIa. In positive feedbackloops, thrombin activates, in addition to factor V and factor VIII, alsofactor XI to factor XIa, whereby factor IX is converted into factor IXa,thus, via the factor IXa/factor VIIIa complex generated in this manner,rapidly producing relatively large amounts of factor Xa. This triggersthe production of large amounts of thrombin, leading to strong thrombusgrowth and stabilizing the thrombus.

In addition, activation of the coagulation system may also occur at inparticular negatively charged surfaces including artificial surfacessuch as vessel prostheses, stents and extracorporeal circulation. On thesurface, initially factor XII is activated to factor XIIa whichsubsequently, via kininogen or glycoprotein Ib, activates factor XIattached to cell surfaces. This leads to further activation of thecoagulation cascade.

In addition, factor XIIa also activates bound plasma prekallikrein toplasma kallikrein. Plasma kallikrein in turn, in a potentiation loop,leads to further factor XII activation, overall resulting inamplification of the initiation of the coagulation cascade. In addition,plasma kallikrein is an important bradikinin-releasing protease which,inter alia, thus leads to increased endothelial permeability. Furthersubstrates that have been described are prorenin and prourokinase, whoseactivation may trigger the regulatory processes of the renin-angiotensinsystem and fibrinolysis.

Uncontrolled activation of the coagulation system or defects in theinhibition of the activation processes may cause formation of localthromboses or embolisms in vessels (arteries, veins, lymph vessels) orheart chambers. This may lead to serious thrombotic or thromboembolicdisorders. In addition, systemic hypercoaguability may lead toconsumption coagulopathy in the context of a disseminated intravasalcoagulation.

In the course of many cardiovascular and metabolic disorders, there isan increased tendency for coagulation and platelet activation owing tosystemic factors such as hyperlipidaemia, diabetes or smoking, owing tochanges in blood flow with stasis, for example in atrial fibrillation,or owing to pathological changes in vessel walls, for exampleendothelial dysfunctions or atherosclerosis. This unwanted and excessivehaemostasis may, by formation of fibrin- and platelet-rich thrombi, leadto thromboembolic disorders and thrombotic complications withlife-threatening conditions. Inflammable processes may also be involvedhere.

Thromboembolic disorders are the most frequent cause of morbidity andmortality in most industrialized countries [Heart Disease: A Textbook ofCardiovascular Medicine, Eugene Braunwald, 5th edition, 1997, W.B.Saunders Company, Philadelphia].

The anticoagulants known from the prior art, for example substances forinhibiting or preventing blood coagulation, have various, frequentlygrave disadvantages. Accordingly, in practice, efficient treatmentmethods or the prophylaxis of thrombotic/thromboembolic disorders isfrequently found to be very difficult and unsatisfactory.

In the therapy and prophylaxis of thromboembolic disorders, use is made,firstly, of heparin which is administered parenterally orsubcutaneously. Because of more favourable pharmacokinetic properties,preference is these days increasingly given to low-molecular-weightheparin; however, the known disadvantages described hereinbelowencountered in heparin therapy cannot be avoided either in this manner.Thus, heparin is orally ineffective and has only a comparatively shorthalf-life. In addition, there is a high risk of bleeding, there may inparticular be cerebral haemorrhages and bleeding in the gastrointestinaltract, and there may be thrombopenia, alopecia medicomentosa orosteoporosis [Pschyrembel, Klinisches Wörterbuch [clinical dictionary],257th edition, 1994, Walter de Gruyter Verlag, page 610, keyword“Heparin”; Römpp Lexikon Chemie, version 1.5, 1998, Georg Thieme VerlagStuttgart, keyword “Heparin”]. Low-molecular-weight heparins do have alower probability of leading to the development of heparin-inducedthrombocytopenia; however, they can likewise only be administeredsubcutaneously. This also applies to fondaparinux, a syntheticallyproduced selective factor Xa inhibitor having a long half-life.

A second class of anticoagulants are the vitamin K antagonists. Theseinclude, for example, 1,3-indanediones and in particular compounds suchas warfarin, phenprocoumon, dicumarol and other cumarin derivativeswhich non-selectively inhibit the synthesis of various products ofcertain vitamin K-dependent coagulation factors in the liver. Owing tothe mechanism of action, the onset of action is very slow (latency tothe onset of action 36 to 48 hours). The compounds can be administeredorally; however, owing to the high risk of bleeding and the narrowtherapeutic index complicated individual adjustment and monitoring ofthe patient are required [J. Hirsch, J. Dalen, D. R. Anderson et al.,“Oral anticoagulants: Mechanism of action, clinical effectiveness, andoptimal therapeutic range” Chest 2001, 119, 8S-21S; J. Ansell, J.Hirsch, J. Dalen et al., “Managing oral anticoagulant therapy” Chest2001, 119, 22S-38S; P. S. Wells, A. M. Holbrook, N. R. Crowther et al.,“Interactions of warfarin with drugs and food” Ann. Intern. Med. 1994,121, 676-683]. In addition, other side-effects such as gastrointestinalproblems, hair loss and skin necroses have been described.

More recent approaches for oral anticoagulants are in various phases ofclinical evaluation or in clinical use; however, they have alsodisplayed disadvantages such as, for example, highly variablebioavailability, liver damage and bleeding complications.

For antithrombotic medicaments, the therapeutic width is of centralimportance: The distance between the therapeutically active dose forcoagulation inhibition and the dose where bleeding may occur should beas big as possible so that maximum therapeutic activity is achieved at aminimum risk profile.

In various in vivo models with, for example, antibodies as factor XIainhibitors, but also in factor XIa knock-out models, the antithromboticeffect with small/no prolongation of bleeding time or extension of bloodvolume was confirmed. In clinical studies, elevated factor XIaconcentrations were associated with an increased event rate. However,factor XI deficiency (haemophilia C), in contrast to factor VIIIa orfactor IXa (haemophilia A and B, respectively), did not lead tospontaneous bleeding and was only noticed during surgical interventionsand traumata. Instead, protection against certain thromboembolic eventswas found.

Furthermore, for many disorders the combination of antithrombotic andantiinflammatory principles may also be particularly attractive toprevent the mutual enhancement of coagulation and inflammation.

Plasma kallikrein is associated with disorders accompanied by increasedvessel permeability as is the case, for example, in diabetic retinopathyand macular oedema.

Diabetic retinopathy, a well-characterized chronic eye disorder, is themost frequent microvascular sequela of type 1 and type 2 diabetesmellitus. It is classified into two forms, non-proliferative retinopathyand proliferative retinopathy which in turn are classified according totheir degree of severity.

Diabetic retinopathy is primarily caused by microvascular deficiency.These is an initial thickening of the basal membrane of the vessels andloss of vascularized pericytes, followed by vascular occlusion andretinal ischaemia. Further development is then controlled by theresulting retinal hypoxia, which causes preretinal neovascularizationand increased vascular permeability with subsequent formation of amacular oedema. All this finally leads to the patient going blind.

From animal models, there are indications that inhibition of plasmakallikrein inhibits increased vascular permeability and may thereforeprevent formation of a macular oedema and/or diabetic retinopathy.

It is therefore an object of the present invention to provide novelcompounds for the treatment of cardiovascular disorders, in particularof thrombotic or thromboembolic and also oedematous disorders, and/orophthalmic disorders, in particular diabetic retinopathy and/or macularoedema, in humans and animals, which compounds have a wide therapeuticbandwidth.

WO 2006/030032 describes inter alia substituted pyridinones asallosteric modulators of the mGluR2 receptor, and WO 2008/079787describes substituted pyridin-2-ones and their use as glucokinaseactivators.

The invention provides compounds of the formula

in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents bromine, chlorine, fluorine, methyl,        difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or        trifluoromethoxy,    -   R⁷ represents bromine, chlorine, fluorine, cyano, nitro,        hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy,        ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl,        3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,    -   R⁸ represents hydrogen, chlorine or fluorine,

-   R² represents hydrogen, bromine, chlorine, fluorine, cyano,    C₁-C₃-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,    2,2-difluoroethyl, 2,2,2-trifluoroethyl, C₁-C₃-alkoxy,    difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy,    2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or    cyclopropyl,

-   R³ represents hydrogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, difluoromethyl,    trifluoromethyl, 1,1-difluoroethyl, 1,1,2,2,2-pentadeuteroethyl,    3,3,3-trifluoro-2-hydroxyprop-1-yl,    3,3,3-trifluoro-2-methoxyprop-1-yl,    3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or    cyclobutyloxy,    -   where alkyl may be substituted by a substituent selected from        the group consisting of fluorine, cyano, hydroxy,        difluoromethyl, trifluoromethyl, methoxy, ethoxy,        difluoromethoxy, trifluoromethoxy, C₃-C₆-cycloalkyl, 4- to        6-membered oxoheterocyclyl, 4- to 6-membered thioheterocyclyl,        1,4-dioxanyl, phenyl and pyridyl,        -   where cycloalkyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of fluorine, hydroxy, methyl, ethyl, methoxy,            ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and            trifluoromethoxy,        -   and        -   where oxoheterocyclyl and thioheterocyclyl may be            substituted by 1 to 2 substituents independently of one            another selected from the group consisting of oxo, fluoro,            methyl, ethyl, difluoromethyl and trifluoromethyl,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl or 5-membered heterocyclyl,        -   where heterocyclyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of oxo, hydroxy, thioxo, sulphanyl, methyl,            difluoromethyl, trifluoromethyl,            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and            2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,    -   R¹¹ and R¹² together with the carbon atoms to which they are        attached form a 5-membered heterocycle,        -   where the heterocycle may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, chlorine, hydroxy, hydroxycarbonyl,            methyl, difluoromethyl, trifluoromethyl,            1,1,2,2,2-pentafluoroethyl,            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and            2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,    -   R¹³ represents hydrogen, chlorine, fluorine, methyl or methoxy,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, and alsothe compounds encompassed by formula (I) and specified hereinafter asworking example(s), and the salts, solvates and solvates of the saltsthereof, to the extent that the compounds encompassed by formula (I) andspecified hereinafter are not already salts, solvates and solvates ofthe salts.

The compounds according to the invention may, depending on theirstructure, exist in different stereoisomeric forms, i.e. in the form ofconfigurational isomers or else optionally as conformational isomers(enantiomers and/or diastereomers, including those in the case ofatropisomers). The present invention therefore encompasses theenantiomers and diastereomers, and the respective mixtures thereof. Thestereoisomerically uniform constituents can be isolated from suchmixtures of enantiomers and/or diastereomers in a known manner;chromatography processes are preferably used for this, in particularHPLC chromatography on an achiral or chiral phase.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all the tautomeric forms.

In the context of the present invention, the term “enantiomericallypure” is to be understood as meaning that the compound in question withrespect to the absolute configuration of the chiral centre is present inan enantiomeric excess of more than 95%, preferably more than 97%. Theenantiomeric excess, ee, is calculated here by evaluating of thecorresponding HPLC chromatogram on a chiral phase using the formulabelow:ee=[E ^(A)(area %)−E ^(B)(area %)]×100%/[E ^(A)(area %)+E ^(B)(area %)](E^(A): major enantiomer, E^(B): minor enantiomer)

The present invention also encompasses all suitable isotopic variants ofthe compounds according to the invention. An isotopic variant of acompound according to the invention is understood here to mean acompound in which at least one atom within the compound according to theinvention has been exchanged for another atom of the same atomic number,but with a different atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the invention are those ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I,¹²⁴I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compoundaccording to the invention, especially those in which one or moreradioactive isotopes have been incorporated, may be beneficial, forexample, for the examination of the mechanism of action or of the activeingredient distribution in the body; due to comparatively easypreparability and detectability, especially compounds labelled with ³Hor ¹⁴C isotopes are suitable for this purpose. Furthermore, theincorporation of isotopes, for example of deuterium, can lead toparticular therapeutic advantages as a consequence of greater metabolicstability of the compound, for example an extension of the half-life inthe body or a reduction in the active dose required; such modificationsof the compounds according to the invention may therefore, in somecases, also constitute a preferred embodiment of the present invention.Isotopic variants of the compounds according to the invention can beprepared by the processes known to those skilled in the art, for exampleby the methods described below and the procedures described in theworking examples, by using corresponding isotopic modifications of therespective reagents and/or starting compounds.

In the context of the present invention, preferred salts arephysiologically acceptable salts of the compounds according to theinvention. Also included, however, are salts which are themselvesunsuitable for pharmaceutical applications but can be used, for example,for the isolation or purification of the compounds according to theinvention.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulphonic acids, for example salts of hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, methanesulphonic acid,ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid,naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid,propionic acid, lactic acid, tartaric acid, malic acid, citric acid,fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases, by way of exampleand with preference alkali metal salts (e.g. sodium and potassiumsalts), alkaline earth metal salts (e.g. calcium and magnesium salts)and ammonium salts derived from ammonia or organic amines having 1 to 16carbon atoms, by way of example and with preference ethylamine,diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

In the context of the invention, solvates refer to those forms of thecompounds according to the invention which, in the solid or liquidstate, form a complex by coordination with solvent molecules. Hydratesare a specific form of solvates in which the coordination is with water.

Moreover, the present invention also encompasses prodrugs of thecompounds according to the invention. The term “prodrugs” includescompounds which may themselves be biologically active or inactive butare converted to compounds according to the invention while resident inthe body (for example metabolically or hydrolytically).

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease, a condition, a disorder, an injury or a health problem, orthe development, the course or the progression of such states and/or thesymptoms of such states. The term “therapy” is understood here to besynonymous with the term “treatment”.

The terms “prevention”, “prophylaxis” or “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease, a condition, a disorder, an injuryor a health problem, or a development or progression of such statesand/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, aninjury or a health problem may be partial or complete.

In the context of the present invention, the substituents, unlessspecified otherwise, are each defined as follows:

Alkyl represents a straight-chain or branched alkyl radical having 1 to5 carbon atoms, preferably 1 to 3 carbon atoms, by way of example andwith preference methyl, ethyl, n-propyl, isopropyl, 2-methylprop-1-yl,n-butyl, tert-butyl and 2,2-dimethylprop-1-yl.

Alkoxy represents a straight-chain or branched alkoxy radical having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, by way of example andwith preference methoxy, ethoxy, n-propoxy, isopropoxy,2-methylprop-1-oxy, n-butoxy and tert-butoxy.

Cycloalkyl represents a monocyclic cycloalkyl group having 3 to 6 carbonatoms, by way of example and with preference cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl may be mentioned for cycloalkyl.

5-membered heterocyclyl in the definition of the radical R⁹ represents asaturated, partially unsaturated or aromatic monocyclic radical having 5ring atoms and up to 4 heteroatoms from the group consisting of S, O andN, where a nitrogen atom may also form an N-oxide, by way of example andwith preference thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, dihydrooxazolyl and dihydroimidazolyl.

5-membered heterocycle in the definition of the radicals R¹¹ and R¹²represents a saturated, partially unsaturated or aromatic monocyclicradical having 5 ring atoms and up to 2 heteroatoms from the groupconsisting of S, O and N, where a nitrogen atom may also form anN-oxide. This 5-membered heterocycle together with the phenyl ring towhich it is attached represents, by way of example and with preference,2,3-dihydro-1-benzothiophen-5-yl, 1,3-dihydro-2-benzothiophen-5-yl,2,3-dihydro-1-benzofuran-5-yl, 1,3-dihydro-2-benzofuran-5-yl,indolin-5-yl, isoindolin-5-yl, 2,3-dihydro-1H-indazol-5-yl,2,3-dihydro-1H-benzimidazol-5-yl, 1,3-dihydro-2,1-benzoxazol-5-yl,2,3-dihydro-1,3-benzoxazol-5-yl, 1,3-dihydro-2,1-benzothiazol-5-yl,2,3-dihydro-1,3-benzothiazol-5-yl, 1H-benzimidazol-5-yl,1H-indazol-5-yl, 1,2-benzoxazol-5-yl, indol-5-yl, isoindol-5-yl,benzofuran-5-yl, benzothiophen-5-yl, 2,3-dihydro-1-benzothiophen-6-yl,1,3-dihydro-2-benzothiophen-6-yl, 2,3-dihydro-1-benzofuran-6-yl,1,3-dihydro-2-benzofuran-6-yl, indolin-6-yl, isoindolin-6-yl,2,3-dihydro-1H-indazol-6-yl, 2,3-dihydro-1H-benzimidazol-6-yl,1,3-dihydro-2,1-benzoxazol-6-yl, 2,3-dihydro-1,3-benzoxazol-6-yl,1,3-dihydro-2,1-benzothiazol-6-yl, 2,3-dihydro-1,3-benzothiazol-6-yl,1H-benzimidazol-6-yl, 1H-indazol-6-yl, 1,2-benzoxazol-6-yl, indol-6-yl,isoindol-6-yl, benzofuran-6-yl and benzothiophen-6-yl.

4- to 6-membered oxoheterocyclyl in the definition of the radical R³represents a saturated monocyclic radical having 4 to 6 ring atoms inwhich one ring atom is an oxygen atom, by way of example and withpreference oxetanyl, tetrahydrofuranyl and tetrahydro-2H-pyranyl.

4- to 6-membered thioheterocyclyl in the definition of the radical R³represents a saturated monocyclic radical having 4 to 6 ring atoms inwhich one ring atom is an sulphur atom, by way of example and withpreference thientanyl, tetrahydrothienyl and tetrahydro-2H-thiopyranyl.

In the formulae of the group which may represent R¹, the end point ofthe line marked by * does not represent a carbon atom or a CH₂ group,but is part of the bond to the atom to which R¹ is attached.

In the formulae of the group which may represent R⁵, the end point ofthe line marked by # does not represent a carbon atom or a CH₂ group,but is part of the bond to the atom to which R⁵ is attached.

Preference is given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents bromine, chlorine, cyano, nitro, methyl,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, ethynyl or cyclopropyl,    -   R⁸ represents hydrogen,

-   R² represents hydrogen, chlorine, fluorine, cyano, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy,    difluoromethoxy or 2,2,2-trifluoroethoxy,

-   R³ represents hydrogen, C₁-C₅-alkyl, ethoxy,    1,1,2,2,2-pentadeuteroethyl or prop-2-yn-1-yl,    -   where C₁-alkyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl,        tetrahydrofuranyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may            be substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl, ethyl, methoxy and trifluoromethyl,        -   and        -   where tetrahydrofuranyl, tetrahydro-2H-pyranyl and            tetrahydro-2H-thiopyranyl may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, methyl and ethyl,    -   and    -   where C₂-C₄-alkyl may be substituted by a substituent selected        from the group consisting of fluorine, hydroxy, trifluoromethyl,        methoxy and trifluoromethoxy,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxazolyl, oxadiazolyl,        thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or        dihydrooxazolyl,        -   where oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,            imidazolyl, triazolyl and dihydrooxazolyl may be substituted            by 1 to 2 substituents independently of one another selected            from the group consisting of oxo, hydroxy, thioxo,            sulphanyl, methyl, trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,    2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl or    1H-indazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl        and 1H-indazol-5-yl may be substituted by 1 to 2 substituents        independently of one another selected from the group consisting        of oxo, chlorine, hydroxycarbonyl, methyl and trifluoromethyl,    -   and    -   where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl        and 1H-indazol-5-yl may be substituted by a substituent selected        from the group consisting of fluorine and methoxy,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents cyano or difluoromethoxy,    -   R⁸ represents hydrogen,

-   R² represents chlorine, cyano, methoxy, ethoxy or difluoromethoxy,

-   R³ represents methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,    -   where methyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,        tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl and cyclohexyl may be            substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl, methoxy and trifluoromethyl,    -   and    -   where ethyl, n-propyl and n-butyl may be substituted by a        substituent selected from the group consisting of fluorine,        methoxy and trifluoromethoxy,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl, triazolyl        or tetrazolyl,        -   where oxadiazolyl and pyrazolyl may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, hydroxy and trifluoromethyl,        -   and        -   where triazolyl may be substituted by a substituent selected            from the group consisting of trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,    -   R¹⁰ represents hydrogen or fluorine,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    2,3-dihydro-1H-benzimidazol-5-yl or 1H-indazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl        may substituted by 1 to 2 substituents independently of one        another selected from the group consisting of oxo and methyl,    -   and    -   where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl may be        substituted by a fluorine substituent,    -   and    -   where the 5-membered heterocycle in 1H-benzimidazol-6-yl may be        substituted by a hydroxycarbonyl substituent,    -   and    -   where the 5-membered heterocycle in        2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an oxo        substituent,    -   and    -   where the 5-membered heterocycle in 1H-indazol-5-yl may be        substituted by a chlorine substituent,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R³ represents hydrogen, C₁-C₅-alkyl, ethoxy,    1,1,2,2,2-pentadeuteroethyl or prop-2-yn-1-yl,    -   where C₁-alkyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl,        tetrahydrofuranyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may            be substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl, ethyl, methoxy and trifluoromethyl,        -   and        -   where tetrahydrofuranyl, tetrahydro-2H-pyranyl and            tetrahydro-2H-thiopyranyl may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, methyl and ethyl,    -   and    -   where C₂-C₄-alkyl may be substituted by a substituent selected        from the group consisting of fluorine, hydroxy, trifluoromethyl,        methoxy and trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R³ represents methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,    -   where methyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,        tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl and cyclohexyl may be            substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl, methoxy and trifluoromethyl,    -   and    -   where ethyl, n-propyl and n-butyl may be substituted by a        substituent selected from the group consisting of fluorine,        methoxy and trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxazolyl, oxadiazolyl,        thiadiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl or        dihydrooxazolyl,        -   where oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,            imidazolyl, triazolyl and dihydrooxazolyl may be substituted            by 1 to 2 substituents independently of one another selected            from the group consisting of oxo, hydroxy, thioxo,            sulphanyl, methyl, trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    Indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,    2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl or    1H-indazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl        and 1H-indazol-5-yl may be substituted by 1 to 2 substituents        independently of one another selected from the group consisting        of oxo, chlorine, hydroxycarbonyl, methyl and trifluoromethyl,    -   and    -   where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl        and 1H-indazol-5-yl may be substituted by a substituent selected        from the group consisting of fluorine and methoxy.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    2,3-dihydro-1H-benzimidazol-5-yl or 1H-indazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl        may be substituted by 1 to 2 substituents independently of one        another selected from the group consisting of oxo and methyl,    -   and    -   where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl may be        substituted by a fluorine substituent,    -   and    -   where the 5-membered heterocycle in 1H-benzimidazol-6-yl may be        substituted by a hydroxycarbonyl substituent,    -   and    -   where the 5-membered heterocycle in        2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an oxo        substituent,    -   and    -   where the 5-membered heterocycle in 1H-indazol-5-yl may be        substituted by a chlorine substituent.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    Indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,    2,3-dihydro-1H-benzimidazol-5-yl or indol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl and indol-5-yl may be        substituted by 1 to 2 substituents independently of one another        selected from the group consisting of oxo, hydroxycarbonyl,        methyl and trifluoromethyl.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents bromine, chlorine, fluorine, methyl,        difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or        trifluoromethoxy,    -   R⁷ represents bromine, chlorine, fluorine, cyano, nitro,        hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy,        ethoxy, difluoromethoxy, trifluoromethoxy, ethynyl,        3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,    -   R⁸ represents hydrogen, chlorine or fluorine,

-   R² represents hydrogen, bromine, chlorine, fluorine, cyano,    C₁-C₃-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,    2,2-difluoroethyl, 2,2,2-trifluoroethyl, C₁-C₃-alkoxy,    difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy,    2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or    cyclopropyl,

-   R³ represents hydrogen, C₁-C₅-alkyl, C₁-C₄-alkoxy, difluoromethyl,    trifluoromethyl, 1,1-difluoroethyl,    3,3,3-trifluoro-2-hydroxyprop-1-yl,    3,3,3-trifluoro-2-methoxyprop-1-yl,    3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or    cyclobutyloxy,    -   where alkyl may be substituted by a substituent selected from        the group consisting of fluorine, cyano, hydroxy,        difluoromethyl, trifluoromethyl, methoxy, ethoxy,        difluoromethoxy, trifluoromethoxy, C₃-C₆-cycloalkyl, 4- to        6-membered oxoheterocyclyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cycloalkyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of fluorine, hydroxy, methyl, ethyl, methoxy,            ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and            trifluoromethoxy,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl or 5-membered heterocyclyl,        -   where heterocyclyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of oxo, hydroxy, methyl, difluoromethyl,            trifluoromethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl            and 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,    -   R¹¹ and R¹² together with the carbon atoms to which they are        attached form a 5-membered heterocycle,        -   where the heterocycle may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, chlorine, hydroxy, hydroxycarbonyl,            methyl, difluoromethyl, trifluoromethyl,            1,1,2,2,2-pentafluoroethyl,            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and            2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl,    -   R¹³ represents hydrogen, chlorine, fluorine or methyl,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents bromine, chlorine, cyano, nitro, methyl,        difluoromethyl, trifluoromethyl, difluoromethoxy,        trifluoromethoxy, ethynyl or cyclopropyl,    -   R⁸ represents hydrogen,

-   R² represents hydrogen, chlorine, fluorine, cyano, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy,    difluoromethoxy or 2,2,2-trifluoroethoxy,

-   R³ represents hydrogen, C₁-C₅-alkyl, ethoxy or prop-2-yn-1-yl,    -   where C₁-alkyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl,        tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl        and pyridyl,        -   where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may            be substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl and ethyl,    -   and    -   where C₂-C₄-alkyl may be substituted by a substituent selected        from the group consisting of fluorine, hydroxy, trifluoromethyl,        methoxy and trifluoromethoxy,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl,        imidazolyl, triazolyl, tetrazolyl or dihydrooxazolyl,        -   where oxadiazolyl, pyrazolyl, imidazolyl, triazolyl and            dihydrooxazolyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of oxo, hydroxy, methyl, trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,    Indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,    2,3-dihydro-1H-benzimidazol-5-yl or indol-5-yl,    -   where 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl,        indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,        2,3-dihydro-1H-benzimidazol-5-yl and indol-5-yl may be        substituted by 1 to 2 substituents independently of one another        selected from the group consisting of oxo, hydroxycarbonyl,        methyl and trifluoromethyl,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents cyano or difluoromethoxy,    -   R⁸ represents hydrogen,

-   R² represents chlorine, cyano, methoxy, ethoxy or difluoromethoxy,

-   R³ represents methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,    -   where methyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,        tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl and cyclohexyl may be            substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy and methyl,    -   and    -   where ethyl, n-propyl and n-butyl may be substituted by a        substituent selected from the group consisting of fluorine,        methoxy and trifluoromethoxy,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl, triazolyl        or tetrazolyl,        -   where oxadiazolyl and pyrazolyl may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, hydroxy and trifluoromethyl,        -   and        -   where triazolyl may be substituted by a substituent selected            from the group consisting of trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,    -   R¹⁰ represents hydrogen or fluorine,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl or    2,3-dihydro-1H-benzimidazol-5-yl,    -   where 2,3-dihydro-1H-indazol-6-yl may be substituted by 1 to 2        substituents independently of one another selected from the        group consisting of oxo and methyl,    -   and    -   where 1H-benzimidazol-6-yl may be substituted by a        hydroxycarbonyl substituent,    -   and    -   where 2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an        oxo substituent,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents cyano or difluoromethoxy,    -   R⁸ represents hydrogen.

Preference is also given to compounds of the formula (I) in which R²represents chlorine, cyano, methoxy, ethoxy or difluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R³ represents C₁-C₅-alkyl, C₁-C₄-alkoxy, difluoromethyl,    trifluoromethyl, 1,1-difluoroethyl,    3,3,3-trifluoro-2-hydroxyprop-1-yl,    3,3,3-trifluoro-2-methoxyprop-1-yl,    3,3,3-trifluoro-2-ethoxyprop-1-yl, prop-2-yn-1-yl, cyclopropyloxy or    cyclobutyloxy,    -   where alkyl may be substituted by a substituent selected from        the group consisting of fluorine, cyano, hydroxy,        difluoromethyl, trifluoromethyl, methoxy, ethoxy,        difluoromethoxy, trifluoromethoxy, C₃-C₆-cycloalkyl, 4- to        6-membered oxoheterocyclyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cycloalkyl may be substituted by 1 to 2 substituents            independently of one another selected from the group            consisting of fluorine, hydroxy, methyl, ethyl, methoxy,            ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy and            trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R³ represents C₁-C₅-alkyl, ethoxy or prop-2-yn-1-yl,    -   where C₁-alkyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, oxetanyl,        tetrahydrofuranyl, tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl        and pyridyl,        -   where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl may            be substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy, methyl and ethyl,    -   and        -   where C₂-C₄-alkyl may be substituted by a substituent            selected from the group consisting of fluorine, hydroxy,            trifluoromethyl, methoxy and trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R³ represents methyl, ethyl, n-propyl, 2-methylprop-1-yl or n-butyl,    -   where methyl may be substituted by a substituent selected from        the group consisting of difluoromethyl, trifluoromethyl,        cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,        tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl,        -   where cyclopropyl, cyclobutyl and cyclohexyl may be            substituted by 1 to 2 substituents independently of one            another selected from the group consisting of fluorine,            hydroxy and methyl,    -   and    -   where ethyl, n-propyl and n-butyl may be substituted by a        substituent selected from the group consisting of fluorine,        methoxy and trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl, triazolyl        or tetrazolyl,        -   where oxadiazolyl and pyrazolyl may be substituted by 1 to 2            substituents independently of one another selected from the            group consisting of oxo, hydroxy and trifluoromethyl,        -   and        -   where triazolyl may be substituted by a substituent selected            from the group consisting of trifluoromethyl and            2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl,    -   R¹⁰ represents hydrogen or fluorine.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl or    2,3-dihydro-1H-benzimidazol-5-yl,    -   where 2,3-dihydro-1H-indazol-6-yl may be substituted by 1 to 2        substituents independently of one another selected from the        group consisting of oxo and methyl,    -   and    -   where 1H-benzimidazol-6-yl may be substituted by a        hydroxycarbonyl substituent,    -   and    -   where 2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an        oxo substituent.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl or    2,3-dihydro-1H-benzimidazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl        may be substituted by 1 to 2 substituents independently of one        another selected from the group consisting of oxo and methyl,    -   and    -   where the 5-membered heterocycle in 1H-benzimidazol-6-yl may be        substituted by a hydroxycarbonyl substituent,    -   and    -   where the 5-membered heterocycle in        2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an oxo        substituent.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents bromine, chlorine, fluorine, methyl,        difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or        trifluoromethoxy,    -   R⁷ represents bromine, chlorine, fluorine, cyano, nitro,        hydroxy, methyl, difluoromethyl, trifluoromethyl, methoxy,        difluoromethoxy, trifluoromethoxy, ethynyl,        3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,    -   R⁸ represents hydrogen, chlorine or fluorine,

-   R² represents hydrogen, bromine, chlorine, fluorine, cyano,    C₁-C₃-alkyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,    2,2-difluoroethyl, 2,2,2-trifluoroethyl, C₁-C₃-alkoxy,    difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy,    2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, methylcarbonyl or    cyclopropyl,

-   R³ represents C₁-C₅-alkyl, difluoromethyl, trifluoromethyl,    1,1-difluoroethyl or prop-2-yn-1-yl,    -   where alkyl may be substituted by a substituent selected from        the group consisting of fluorine, cyano, hydroxy,        difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy,        trifluoromethoxy, C₃-C₆-cycloalkyl, 4- to 6-membered        oxoheterocyclyl, phenyl and pyridyl,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl or 5-membered heterocyclyl,        -   where heterocyclyl may be substituted by 1 to 2 substituents            selected from the group consisting of oxo, hydroxy, methyl,            difluoromethyl and trifluoromethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,    -   R¹¹ and R¹² together with the carbon atoms to which they are        attached form a 5-membered heterocycle,        -   where the heterocycle may be substituted by 1 to 2            substituents selected from the group consisting of oxo,            hydroxy, methyl, difluoromethyl, trifluoromethyl and            1,1,2,2,2-pentafluoroethyl,    -   R¹³ represents hydrogen, chlorine, fluorine or methyl,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents bromine, chlorine, cyano, nitro, difluoromethyl,        trifluoromethyl, trifluoromethoxy, ethynyl or cyclopropyl,    -   R⁸ represents hydrogen,

-   R² represents hydrogen, chlorine, fluorine, cyano, difluoromethyl,    trifluoromethyl, 2,2,2-trifluoroethyl, methoxy or ethoxy,

-   R³ represents C₁-C₅-alkyl or prop-2-yn-1-yl,    -   where C₁-alkyl may be substituted by a substituent selected from        the group consisting of cyclopropyl, phenyl and pyridyl,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl,        imidazolyl, triazolyl or tetrazolyl,        -   where oxadiazolyl, pyrazolyl, imidazolyl and triazolyl may            be substituted by 1 to 2 substituents selected from the            group consisting of oxo, hydroxy, methyl and            trifluoromethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl or    2,3-dihydro-1H-indazol-5-yl,    -   where 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl and        2,3-dihydro-1H-indazol-5-yl may be substituted by 1 to 2        substituents selected from the group consisting of oxo, methyl        and trifluoromethyl,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents cyano or trifluoromethyl,    -   R⁸ represents hydrogen,

-   R² represents hydrogen, chlorine, fluorine, cyano,    2,2,2-trifluoroethyl, methoxy or ethoxy,

-   R³ represents methyl, ethyl or 2-methylprop-1-yl,    -   where methyl may be substituted by a cyclopropyl substituent,

-   R⁴ represents hydrogen,

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl,        imidazolyl, triazolyl or tetrazolyl,        -   where oxadiazolyl, pyrazolyl, imidazolyl and triazolyl may            be substituted by 1 to 2 substituents selected from the            group consisting of oxo, hydroxy, methyl and            trifluoromethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl,

-   or

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl and 1H-benzimidazol-6-yl,    -   where 2,3-dihydro-1H-indazol-6-yl and 1H-benzimidazol-6-yl may        be substituted by 1 to 2 substituents selected from the group        consisting of oxo, methyl and trifluoromethyl,        and the salts thereof, solvates thereof and the solvates of the        salts thereof.

Preference is also given to compounds of the formula (I) in which

-   R¹ represents a group of the formula

-   -   where * is the point of attachment to the oxopyridine ring,    -   R⁶ represents chlorine,    -   R⁷ represents cyano or trifluoromethoxy,    -   R⁸ represents hydrogen.

Preference is also given to compounds of the formula (I) in which R²represents hydrogen, chlorine, cyano, 2,2,2-trifluoroethyl, methoxy orethoxy.

Preference is also given to compounds of the formula (I) in which R³represents methyl, ethyl or 2-methylprop-1-yl, where methyl may besubstituted by a cyclopropyl substituent.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents a group of the formula

-   -   where # is the point of attachment to the nitrogen atom,    -   R⁹ represents hydroxycarbonyl, oxadiazolyl, pyrazolyl,        imidazolyl, triazolyl or tetrazolyl,        -   where oxadiazolyl, pyrazolyl, imidazolyl and triazolyl may            be substituted by 1 to 2 substituents selected from the            group consisting of oxo, hydroxy, methyl and            trifluoromethyl,            -   where methyl may be substituted by a methoxy                substituent,    -   R¹⁰ represents hydrogen, chlorine, fluorine or methyl.

Preference is also given to compounds of the formula (I) in which

-   R⁵ represents 2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl or    2,3-dihydro-1H-indazol-5-yl,    -   where the 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl,        1H-benzimidazol-6-yl and 2,3-dihydro-1H-indazol-5-yl may be        substituted by 1 to 2 substituents selected from the group        consisting of oxo, methyl and trifluoromethyl.

Preference is also given to compounds of the formula (I) in which R⁵represents 2,3-dihydro-1H-indazol-6-yl or 1H-benzimidazol-6-yl, where2,3-dihydro-1H-indazol-6-yl and 1H-benzimidazol-6-yl may be substitutedby 1 to 2 substituents selected from the group consisting of oxo, methyland trifluoromethyl.

Preference is also given to compounds of the formula (I) in which R⁵represents 2,3-dihydro-1H-indazol-6-yl or 1H-benzimidazol-6-yl, wherethe 5-membered heterocycle in 2,3-dihydro-1H-indazol-6-yl and1H-benzimidazol-6-yl may be substituted by 1 to 2 substituents selectedfrom the group consisting of oxo, methyl and trifluoromethyl.

Preference is also given to compounds of the formula (Ia)

in which R¹, R², R³, R⁴ and R⁵ are as defined above.

The invention further provides a process for preparing the compounds ofthe formula (I), or the salts thereof, solvates thereof and the solvatesof the salts thereof, wherein

[A] the compounds of the formula

in whichR¹, R², R³, R⁴ and R¹⁰ have the meaning given above andR¹⁴ represents tert-butyl,are reacted with an acid to give compounds of the formula

in whichR¹, R², R³, R⁴ and R¹⁰ have the meaning given above andR⁹ represents hydroxycarbonyl,or[B] the compounds of the formula

in whichR¹, R², R³, R⁴ and R¹⁰ have the meaning given above andR¹⁴ represents methyl or ethyl,are reacted with a base to give compounds of the formula

in whichR¹, R², R³, R⁴ and R¹⁰ have the meaning given above andR⁹ represents hydroxycarbonyl,or[C] the compounds of the formula

in whichR¹, R² and R³ have the meaning given above,are reacted with compounds of the formula

in whichR⁴ and R⁵ have the meaning given above,in the presence of a dehydrating agent to give compounds of the formula(I),or[D] the compounds of the formula

in whichR², R³, R⁴ and R⁵ have the meaning given above andX¹ represents chlorine, bromine or iodine,are reacted with compounds of the formulaR¹-Q  (VI),in whichR¹ has the meaning given above andQ represents —B(OH)₂, a boronic ester, preferably boronic acid pinacolester, or —BF₃ ⁻K⁺,under Suzuki coupling conditions to give compounds of the formula (I).

The compounds of the formula (Ib) are a subset of the compounds of theformula (I).

The compounds of the formulae (IIa) and (IIb) together form the group ofthe compounds of the formula (II).

The reaction according to process [A] is generally carried out in inertsolvents, preferably in a temperature range from room temperature to 60°C. at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride or1,2-dichloroethane, or ethers such as tetrahydrofuran or dioxane,preference being given to dichloromethane.

Acids are, for example, trifluoroacetic acid or hydrogen chloride indioxane, preference being given to trifluoroacetic acid.

The reaction according to process [B] is generally carried out in inertsolvents, preferably in a temperature range from room temperature up toreflux of the solvents at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride or1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such asdiethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, or other solvents such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, ormixtures of solvent with water; preference is given to a mixture oftetrahydrofuran and water or a mixture of methanol and water.

Bases are, for example, alkali metal hydroxides such as sodiumhydroxide, lithium hydroxide or potassium hydroxide, or alkali metalcarbonates such as caesium carbonate, sodium carbonate or potassiumcarbonate, or alkoxides such as potassium tert-butoxide or sodiumtert-butoxide, preference being given to lithium hydroxide or caesiumcarbonate.

The reaction according to process [C] is generally carried out in inertsolvents, if appropriate in the presence of a base, preferably in atemperature range from 0° C. to room temperature at atmosphericpressure.

Suitable dehydrating agents here are, for example, carbodiimides such asN,N′-diethyl-, N,N′-dipropyl-, N,N′-diisopropyl-,N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)(optionally in the presence of pentafluorophenol (PFP)),N-cyclohexylcarbodiimid-N′-propyloxymethyl-polystyrene (PS-carbodiimide)or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazoliumcompounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)phosphoryl chloride orbenzotriazolyloxytri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU),(benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) orO-(7-azabenzotriazol-1 tetramethyluronium hexafluorophosphate (HATU), or1-hydroxybenzotriazole (HOBt), orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), or mixtures of these, with bases. The condensation is preferablycarried out using HATU.

Bases are, for example, alkali metal carbonates such as sodium carbonateor potassium carbonate, or sodium bicarbonate or potassium bicarbonate,or organic bases such as trialkylamines, for example triethylamine,N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine ordiisopropylethylamine. The condensation is preferably carried out usingdiisopropylethylamine.

Inert solvents are, for example, halogenated hydrocarbons such asdichloromethane or trichloromethane, hydrocarbons such as benzene, orother solvents such as nitromethane, dioxane, dimethylformamide,dimethyl sulphoxide or acetonitrile. It is also possible to use mixturesof the solvents. Particular preference is given to dimethylformamide.

The reaction according to process [D] is generally carried out in inertsolvents, in the presence of a catalyst, optionally in the presence ofan additional reagent, optionally in a microwave, preferably in atemperature range from room temperature to 150° C. at atmosphericpressure to 3 bar.

Catalysts are, for example, palladium catalysts customary for Suzukireaction conditions; preference is given to catalysts such asdichlorobis(triphenylphosphine)palladium,tetrakistriphenylphosphinepalladium(0), palladium(II)acetate/triscyclohexylphosphine, tris(dibenzylideneacetone)dipalladium,bis(diphenylphosphaneferrocenyl)palladium(II) chloride,1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-napththoquinone)palladiumdimer,allyl(chloro)(1,3-dimesityl-1,3-dihydro-2H-imidazol-2-ylidene)palladium,palladium(II)acetate/dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)phosphine,[1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloridemonodichloromethane adduct or XPhos precatalyst[(2′-aminobiphenyl-2-yl)(chloro)palladiumdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (1:1)],preference is given to tetrakistriphenylphosphinepalladium(0),[1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloridemonodichloromethane adduct or XPhos precatalyst[(2′-aminobiphenyl-2-yl)(chloro)palladiumdicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (1:1)].

Additional reagents are, for example, potassium acetate, caesiumcarbonate, potassium carbonate or sodium carbonate, potassiumtert-butoxide, caesium fluoride or potassium phosphate, which may bepresent in aqueous solution; preferred are additional reagents such aspotassium carbonate or aqueous potassium phosphate solution.

Inert solvents are, for example, ethers such as dioxane, tetrahydrofuranor 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene,or carboxamides such as dimethylformamide or dimethylacetamide, alkylsulphoxides such as dimethyl sulphoxide, order N-methylpyrrolidone oracetonitrile, or mixtures of the solvents with alcohols such as methanolor ethanol and/or water; preference is given to tetrahydrofuran, dioxaneor acetonitrile.

The compounds of the formula (IV) are known, can be synthesized from thecorresponding starting compounds by known processes or can be preparedanalogously to the processes described in the Examples section.

The compounds of the formula (VI) are known or can be synthesized byknown processes from the appropriate starting materials.

The compounds of the formula (II) are known or can be prepared byreacting compounds of the formula

in whichR¹, R² and R³ have the meaning given above,with compounds of the formula

in whichR⁴ and R¹⁰ have the meaning given above andR¹⁴ represents methyl, ethyl or tert-butyl,in the presence of a dehydrating agent.

The reaction is carried out as described for process [C].

The compounds of the formula (VII) are known, can be synthesized fromthe corresponding starting compounds by known processes or can beprepared analogously to the processes described in the Examples section.

The compounds of the formula (III) are known or can be prepared by

[E] reacting compounds of the formula

in whichR¹, R² and R³ have the meaning given above andR¹⁵ represents tert-butyl,with an acidor[F] reacting compounds of the formula

in whichR¹, R² and R³ have the meaning given above andR¹⁵ represents methyl, ethyl or benzyl,with a base.

The compounds of the formulae (VIIIa) and (VIIIb) together form thegroup of the compounds of the formula (VIII).

The reaction according to process [E] is carried out as described forprocess [A].

The reaction according to process [F] is carried out as described forprocess [B].

The compounds of the formula (VIII) are known or can be prepared by

[G] reacting compounds of the formula

in whichR¹ and R² have the meaning given above,with compounds of the formula

in whichR³ has the meaning given above,R¹⁵ represents methyl, ethyl, benzyl or tert-butyl andX² represents chlorine, bromine, iodine, methanesulphonyloxy ortrifluoromethanesulphonyloxy,or[H] reacting compounds of the formula

in whichR² and R³ have the meaning given above,R¹⁵ represents methyl, ethyl, benzyl or tert-butyl andX³ represents chlorine, bromine or iodine,with compounds of the formula (VI) under Suzuki coupling conditions.

The reaction according to process [G] is generally carried out in inertsolvents, optionally in the presence of a base, preferably in atemperature range from room temperature to reflux of the solvents atatmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride or1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such asdiethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, or other solvents such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, ormixtures of solvent with water; preference is given todimethylformamide.

Bases are, for example, alkali metal hydroxides such as sodiumhydroxide, lithium hydroxide or potassium hydroxide, or alkali metalcarbonates such as caesium carbonate, sodium carbonate or potassiumcarbonate, or potassium tert-butoxide or sodium tert-butoxide, sodiumhydride or a mixture of these bases or a mixture of sodium hydride andlithium bromide; preference is given to potassium carbonate or sodiumhydride.

The compounds of the formula (X) are known or can be synthesized byknown processes from the appropriate starting materials.

The reaction according to process [H] is carried out as described forprocess [D].

Further processes which can be used to prepare the compounds of theformula (VIII) can be found under the starting materials in Examples32.1A-C, 41.1A-C, 43.1B, 43.1C, 44.1B and 44.1C.

The compounds of the formula (IX) are known or can be prepared byreacting compounds of the formula

in whichR¹ and R² have the meaning given above,with pyridinium hydrochloride or pyridinium hydrobromide.

The reaction is generally carried out in inert solvents, preferably in atemperature range of from 80° C. to 120° C. at atmospheric pressure.

Inert solvents are, for example, hydrocarbons such as benzene, or othersolvents such as nitromethane, dioxane, dimethylformamide, dimethylsulphoxide or acetonitrile. It is also possible to use mixtures of thesolvents. Particular preference is given to dimethylformamide.

The compounds of the formula (XII) are known or can be prepared byreacting compounds of the formula

in whichR² has the meaning given above andX⁴ represents chlorine, bromine or iodine,with compounds of the formula (VI) under Suzuki coupling conditions.

The reaction is carried out as described for process [D].

The compounds of the formula (XIII) are known or can be synthesized byknown processes from the appropriate starting materials.

The compounds of the formula (XI) are known or can be prepared byreacting compounds of the formula

in whichR² has the meaning given above andX³ represents chlorine, bromine or iodine,with compounds of the formula (X).

The reaction is carried out as described for process [G].

The compounds of the formula (XIV) are known or can be synthesized byknown processes from the appropriate starting materials.

The compounds of the formula (V) are known or can be prepared byreacting compounds of the formula

in whichR² and R³ have the meaning given above andX¹ represents chlorine, bromine or iodine,with compounds of the formula (IV) in the presence of a dehydratingagent.

The reaction is carried out as described for process [C].

The compounds of the formula (XV) are known or can be prepared by

[I] reacting compounds of the formula

in whichR² and R³ have the meaning given above,R¹⁶ represents tert-butyl andX¹ represents chlorine, bromine or iodine,with an acidor[J] reacting compounds of the formula

in whichR² and R³ have the meaning given above,R¹⁶ represents methyl, ethyl or benzyl andX¹ represents chlorine, bromine or iodine,with a base.

The compounds of the formulae (XVIa) and (XVIb) together form the groupof the compounds of the formula (XVI).

The reaction according to process [I] is carried out as described forprocess [A].

The reaction according to process [J] is carried out as described forprocess [B].

The compounds of the formula (XVI) are known or can be prepared byreacting compounds of the formula

in whichR² has the meaning given above andX¹ represents chlorine, bromine or iodine,with compounds of the formula

in whichR³ has the meaning given above,R¹⁶ represents methyl, ethyl, benzyl or tert-butyl andX⁵ represents chlorine, bromine, iodine, methanesulphonyloxy ortrifluoromethanesulphonyloxy.

The reaction is carried out as described for process [G].

The compounds of the formulae (XVII) and (XVIII) are known or can besynthesized by known processes from the appropriate starting materials.

In an alternative process, the compounds of the formula (VIII) can beprepared by reacting compounds of the formula

in whichR¹ and R² have the meaning given above andR¹⁵ represents methyl, ethyl, benzyl or tert-butyl,with compounds of the formulaR³—X⁶  (XX),in whichR³ has the meaning given above and

-   X⁶ represents chlorine, bromine, iodine, methanesulphonyloxy,    trifluoromethanesulphonyloxy or para-toluenesulphonyloxy.

The reaction is generally carried out in inert solvents, if appropriatein the presence of a base, preferably in a temperature range from −78°C. to room temperature at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such asdichloromethane, trichloromethane, carbon tetrachloride or1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such asdiethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, or other solvents such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, ormixtures of solvent with water; preference is given to tetrahydrofuran.

Bases are, for example, potassium tert-butoxide or sodium tert-butoxide,sodium hydride, N-butyllithium or bis(trimethylsilyl)lithium amide,preference is given to bis(trimethylsilyl)lithium amide.

The compounds of the formula (XIX) are known or can be synthesized bythe processes described above, for example process [G], from theappropriate starting materials.

The compounds of the formula (XX) are known or can be synthesized byknown processes from the appropriate starting materials.

In an alternative process, the compounds of the formula (III) can beprepared by reacting compounds of the formula

in whichR¹ and R² have the meaning given above,with compounds of the formula

in whichR³ has the meaning given above andX⁷ represents chlorine, bromine or iodine.

The reaction is generally carried out in inert solvents, if appropriatein the presence of a base, preferably in a temperature range from −10°C. to 90° C. at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons, such asdichloromethane, trichloromethane, carbon tetrachloride or1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such asdiethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane ortetrahydrofuran, or other solvents such as dimethylformamide,dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, ormixtures of solvent with water; preference is given to tetrahydrofuran.

Bases are, for example, potassium tert-butoxide or sodium tert-butoxide,sodium hydride or bis(trimethylsilyl)lithium amide or a mixture ofmagnesium di-tert-butoxide and potassium tert-butoxide, preference isgiven to a mixture of magnesium di-tert-butoxide and potassiumtert-butoxide.

The compounds of the formula (XXI) are known or can be synthesized byknown processes from the appropriate starting materials.

In an alternative process, the compounds of the formula (XV) can beprepared by reacting compounds of the formula

in whichR² has the meaning given above andX¹ represents chlorine, bromine or iodine,with compounds of the formula

in whichR³ has the meaning given above andX⁸ represents chlorine, bromine or iodine.

The reaction is carried out as described for the reaction of compoundsof the formula (IX) with compounds of the formula (XXI).

The compounds of the formula (XXII) are known or can be synthesized byknown processes from the appropriate starting materials.

The preparation of the starting compounds and of the compounds of theformula (I) can be illustrated by the synthesis scheme below.

The compounds according to the invention have an unforeseeable usefulspectrum of pharmacological and pharmacokinetic activity. They arecompounds modulating the proteolytic activity of the serine proteaseFXIa. The compounds according to the invention inhibit the enzymaticcleavage of substrates playing an essential role in the activation ofthe blood coagulation cascade and platelet aggregation. Furthermore,some of the compounds also inhibit plasma kallikrein.

They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of diseases in humans and animals.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular cardiovascular disorders, preferably thromboticor thromboembolic disorders and/or thrombotic or thromboemboliccomplications, and/or ophthalmologic disorders, in particular ofdiabetic retinopathy or macular oedema, and/or inflammatory disorders,in particular those associated with excess plasma kallikrein activity.

“Thromboembolic disorders” in the sense of the present invention includein particular disorders such as acute coronary syndrome (ACS),ST-segment elevation myocardial infarction (STEMI) and non-ST-segmentelevation myocardial infarction (non-STEMI), stable angina pectoris,unstable angina pectoris, reocclusions and restenoses after coronaryinterventions such as angioplasty, stent implantation or aortocoronarybypass, peripheral arterial occlusion diseases, pulmonary embolisms,venous thromboses, in particular in deep leg veins and renal veins,transitory ischaemic attacks and also thrombotic and thromboembolicstroke.

Accordingly, the compounds according to the invention are also suitablefor the prevention and treatment of cardiogenic thromboembolisms suchas, for example, brain ischaemias, stroke and systemic thromboembolismsand ischaemias, in patients with acute, intermittent or persistentcardiac arrhythmias such as, for example, atrial fibrillation, and thoseundergoing cardioversion, furthermore in patients with heart valvedisorders or with artificial heart valves.

In addition, the compounds according to the invention are suitable forthe treatment and prevention of disseminated intravascular coagulation(DIC) which may occur inter alia associated with sepsis, but also owingto surgical interventions, tumour disorders, burns or other injuries andmay lead to severe organ damage by microthrombosis.

Thromboembolic complications furthermore occur in microangiopathichaemolytical anaemias and by the blood coming into contact with foreignsurfaces in the context of extracorporeal circulation such as, forexample, haemodialysis, ECMO (“extracorporeal membrane oxygenation”),LVAD (“left ventricular assist device”) and similar methods, AVfistulas, vascular and heart valve prostheses.

Moreover, the compounds according to the invention are also used forinfluencing wound healing, for the prophylaxis and/or treatment ofatherosclerotic vascular disorders and inflammatory disorders, such asrheumatic disorders of the locomotive system, coronary heart diseases,of heart failure, of hypertension, of inflammatory disorders such as,for example, asthma, inflammatory pulmonary disorders,glomerulonephritis and inflammatory intestinal disorders such as, forexample, Crohn's disease or ulcerative colitis, and additionally alsofor the prophylaxis and/or treatment of dementia disorders such as, forexample, Alzheimer's disease. Moreover, the compounds according to theinvention can be used for inhibiting tumour growth and the formation ofmetastases, for microangiopathies, age-related macular degeneration,diabetic retinopathy, diabetic nephropathy and other microvasculardisorders, and also for the prevention and treatment of thromboemboliccomplications, such as, for example, venous thromboembolisms, for tumourpatients, in particular those undergoing major surgical interventions orchemo- or radiotherapy.

The compounds according to the invention are also suitable formodulating disorders causing high vascular permeability andinflammation, for example hereditary angiooedema (HAE) which is due todysregulation of vascular permeability triggered by excess plasmakallikrein activation.

Furthermore, the compounds according to the invention, in particularthose acting on plasma kallikrein, are suitable for use in lungtransplantations, orthotopic liver transplantations, complicationassociated with CABG (coronary artery bypass graft) operations. Thecompounds according to the invention are furthermore suitable forprotecting organs during transplantation.

Moreover, the compounds according to the invention are also suitable forthe prophylaxis and/or treatment of pulmonary hypertension.

The term “pulmonary hypertension” includes certain forms of pulmonaryhypertension, as determined, for example, by the World HealthOrganization (WHO). Examples which may be mentioned are pulmonaryarterial hypertension, pulmonary hypertension associated with disordersof the left heart, pulmonary hypertension associated with pulmonarydisorders and/or hypoxia and pulmonary hypertension owing to chronicthromboembolisms (CTEPH).

“Pulmonary arterial hypersion” comprises idiopathic pulmonary arterialhypertension (IPAH, formally also referred to as primary pulmonaryhypertension), familial pulmonary arterial hypertension (FPAH) andassociated pulmonary-arterial hypertension (APAH), which is associatedwith collagenoses, congenital systemic-pulmonary shunt vitia, portalhypertension, HIV infections, the ingestion of certain drugs andmedicaments, with other disorders (thyroid disorders, glycogen storagedisorders, Morbus Gaucher, hereditary teleangiectasia,haemoglobinopathies, myeloproliferative disorders, splenectomy), withdisorders having a significant venous/capillary contribution, such aspulmonary-venoocclusive disorder and pulmonary-capillaryhaemangiomatosis, and also persisting pulmonary hypertension ofneonatants.

Pulmonary hypertension associated with disorders of the left heartcomprises a diseased left atrium or ventricle and mitral or aorta valvedefects.

Pulmonary hyptertension associated with pulmonary disorders and/orhypoxia comprises chronic obstructive pulmonary disorders, interstitialpulmonary disorder, sleep apnoea syndrome, alveolar hypoventilation,chronic high-altitude sickness and inherent defects.

Pulmonary hypertension owing to chronic thromboembolisms (CTEPH)comprises the thromboembolic occlusion of proximal pulmonary arteries,the thromboembolic occlusion of distal pulmonary arteries andnon-thrombotic pulmonary embolisms (tumour, parasites, foreign bodies).

The present invention furthermore provides the use of the compoundsaccording to the invention for preparing medicaments for the treatmentand/or prophylaxis of pulmonary hypertension associated withsarcoidosis, histiocytosis X and lymphangiomatosis.

Moreover, the substances according to the invention may also be suitablefor treating pulmonary and hepatic fibroses.

Moreover, the compounds according to the invention may also be suitablefor the treatment and/or prophylaxis of sepsis (or septicaemia),systemic inflammatory syndrome (SIRS), septic organ dysfunction, septicorgan failure and multiorgan failure, acute respiratory distresssyndrome (ARDS), acute lung injury (ALI), septic shock, DIC(disseminated intravascular coagulation or consumption coagulopathy)and/or septic organ failure.

“Sepsis” is defined as the presence of an infection and a systemicinflammatory response syndrome (hereinbelow referred to as “SIRS”). SIRSoccurs during infections, but also during other states such as injuries,burns, shock, surgical interventions, ischaemia, pancreatitis,reanimation or tumours. The definition of the ACCP/SCCM ConsensusConference Committee from 1992 (Crit Care Med 1992; 20:864-874)describes the diagnosis symptoms and measuring parameters required forthe diagnosis of “SIRS” (inter alia body temperature change, increasedpulse, breathing difficulties and changed blood picture). The later(2001) SCCM/ESICM/ACCP/ATS/SIS International Sepsis DefinitionsConference essentially kept the criteria, but fine-tuned details (Levyet al., Crit Care Med 2003; 31:1250-1256).

In the course of sepsis, there may be a generalized activation of thecoagulation system (disseminated intravascular coagulation orconsumption coagulopathy, hereinbelow referred to as “DIC”) withmicrothrombosis in various organs and secondary haemorrhagiccomplications. Moreover, there may be endothelial damage with increasedpermeability of the vessels and seeping of fluids and proteins into theextravasal lumen. As the sepsis progresses, there may be failure of anorgan (for example kidney failure, liver failure, respiratory failure,central-nervous deficits and cardiovascular failure) or multiorganfailure. “Septic shock” is the occurrence of treatment-requiringhypotension which facilitates further organ damage and is associatedwith a worsening of the prognosis.

Pathogens can be bacteria (gram-negative and gram-positive), fungi,viruses and/or eukaryotes. The site of entry or primary infection may bepneumonia, an infection of the urinary tract or peritonitis, forexample. The infection may, but need not necessarily, be associated withbacteriaemia.

DIC and/or SIRS may occur during sepsis, but also as a result ofsurgical interventions, tumour disorders, burns or other injuries. Inthe case of DIC, there is a massive activation of the coagulation systemat the surface of damaged endothelial cells, the surfaces of foreignbodies or injured extravascular tissue. As a consequence, there iscoagulation in small vessels of various organs with hypoxia andsubsequent organ dysfunction. A secondary effect is the consumption ofcoagulation factors (for example factor X, prothrombin and fibrinogen)and platelets, which reduces the coagulability of the blood and mayresult in heavy bleeding.

Therapy of sepsis consists, firstly, in the thorough elimination of theinfectious cause, for example by operative focal reconstruction andantibiosis. Secondly, it consists in temporary intensive medical supportof the affected organ systems. Treatments of the different stages ofthis disease have been described, for example, in the followingpublication (Dellinger et al., Crit Care Med 2004; 32:858-873). Thereare no proven effective treatments for DIC.

“Ophthalmic disorders” in the context of the present invention includein particular disorders such as diabetic retinopathy, diabetic macularoedema (DME), macular oedema, macular oedema associated with retinalvein occlusion, age-related macular degeneration (AMD), choroidalneovascularization (CNV), choroidal neovascular membranes (CNVM),cystoid macula oedema (CME), epiretinal membranes (ERM) and maculaperforations, myopia-associated choroidal neovascularization, angioidstreaks, vascular streaks, retina detachment, atrophic changes of theretinal pigment epithelium, hypertrophic changes of the retinal pigmentepithelium, retinal vein occlusion, choroidal retinal vein occlusion,retinitis pigmentosa, Stargardt's disease, retinopathy of prematurity,glaucoma, inflammatory eye disorder such as uveitis, scleritis orendophthalmitis, cataract, refraction anomalies such as myopia,hyperopia or astigmatism and keratoconus, disorders of the anterior eyesuch as corneal angiogenesis as sequela of, for example ceratitis,cornea transplantation or keratoplasty, corneal angiogenesis as sequelaof hypoxia (for example by excessive use of contact lenses), pterygiumconjunctivae, subcorneal oedema and intracorneal oedema.

The present invention further provides medicaments comprising a compoundaccording to the invention and one or more further active compounds,especially for the treatment and/or prophylaxis of the disordersmentioned above. Preferred examples of suitable active compoundcombinations include:

-   -   Antibiotic therapy

Various antibiotics or antifungal medicament combinations are suitable,either as calculated therapy (prior to the presence of the microbialdiagnosis) or as specific therapy.

-   -   Fluid therapy        for example crystalloids or colloidal fluids.    -   Vasopressors        for example norepinephrins, dopamines or vasopressin    -   Inotropic therapy        for example dobutamine    -   Corticosteroids        for example hydrocortisone, or fludrocortisone    -   Recombinant human activated protein C        Xigris    -   Blood products        for example erythrocyte concentrates, platelet concentrates,        erythropoietin or fresh frozen plasma    -   Artificial ventilation in the case of sepsis-induced acute lung        injury (ALI)    -   or acute respiratory distress syndrome (ARDS)        for example permissive hypercapnia, reduced tidal volumes    -   Sedation, analgesia and neuromuscular blockade        Sedation: for example diazepam, lorazepam, midazolam or        propofol. Opioids: for example fentanyl, hydromorphone,        morphine, meperidine or remifentanil. NSAIDs: for example        ketorolac, ibuprofen or acetaminophen. Neuromuscular blockade:        for example pancuronium    -   Glucose control        for example insulin, glucose    -   Renal replacement methods        for example continuous veno-venous haemofiltration or        intermittent haemodialysis. Low doses of dopamine for renal        protection.    -   Anticoagulants        for example for thrombosis prophylaxis or renal replacement        methods, for example unfractionated heparins,        low-molecular-weight heparins, heparinoids, hirudin, bivalirudin        or argatroban.    -   Bicarbonate therapy    -   Stress ulcer prophylaxis        for example H2-receptor inhibitors, antacids.

In addition, the compounds according to the invention can also be usedfor preventing coagulation ex vivo, for example for preserving blood andplasma products, for cleaning/pretreating catheters and other medicalauxiliaries and instruments, for coating synthetic surfaces of medicalauxiliaries and instruments used in vivo or ex vivo or for biologicalsamples which may comprise factor XIa and/or plasma kallikrein.

The present invention further provides for the use of the compoundsaccording to the invention for the treatment and/or prophylaxis ofdisorders, in particular the disorders mentioned above.

The present invention further provides for the use of the compoundsaccording to the invention for producing a medicament for treatmentand/or prophylaxis of disorders, in particular the disorders mentionedabove.

The present invention further provides a method for the treatment and/orprophylaxis of disorders, especially the disorders mentioned above,using a therapeutically effective amount of a compound according to theinvention.

The present invention further provides medicaments comprising a compoundaccording to the invention and one or more further active compounds.

The present invention furthermore provides a method for preventing thecoagulation of blood in vitro, in particular in banked blood orbiological samples which may comprise factor XIa and/or plasmakallikrein, which method is characterized in that an anticoagulatoryeffective amount of the compound according to the invention is added.

The present invention further provides medicaments comprising a compoundaccording to the invention and one or more further active compounds,especially for the treatment and/or prophylaxis of the disordersmentioned above. Preferred examples of suitable active compoundcombinations include:

-   -   lipid-lowering substances, in particular        HMG-CoA-(3-hydroxy-3-methylglutaryl-coenzyme A) reductase        inhibitors such as, for example, lovastatin (Mevacor),        simvastatin (Zocor), pravastatin (Pravachol), fluvastatin        (Lescol) and atorvastatin (Lipitor);    -   coronary therapeutics/vasodilatators, in particular ACE        (angiotensin converting enzyme) inhibitors such as, for example,        captopril, lisinopril, enalapril, ramipril, cilazapril,        benazepril, fosinopril, quinapril and perindopril, or AII        (angiotensin II) receptor antagonists such as, for example,        embusartan, losartan, valsartan, irbesartan, candesartan,        eprosartan and temisartan, or β-adrenoceptor antagonists such        as, for example, carvedilol, alprenolol, bisoprolol, acebutolol,        atenolol, betaxolol, carteolol, metoprolol, nadolol, penbutolol,        pindolol, propanolol and timolol, or alpha-1-adrenoceptor        antagonists such as, for example, prazosine, bunazosine,        doxazosine and terazosine, or diuretics such as, for example,        hydrochlorothiazide, furosemide, bumetanide, piretanide,        torasemide, amiloride and dihydralazine, or calcium channel        blockers such as, for example, verapamil and diltiazem, or        dihydropyridine derivatives such as, for example, nifedipin        (Adalat) and nitrendipine (Bayotensin), or nitro preparations        such as, for example, isosorbide 5-mononitrate, isosorbide        dinitrate and glycerol trinitrate, or substances causing an        increase in cyclic guanosine monophosphate (cGMP) such as, for        example, stimulators of soluble guanylate cyclase, for example        riociguat;    -   plasminogen activators (thrombolytics/fibrinolytics) and        compounds which promote thrombolysis/fibrinolysis such as        inhibitors of the plasminogen activator inhibitor (PAI        inhibitors) or inhibitors of the thrombin-activated fibrinolysis        inhibitor (TAFI inhibitors) such as, for example, tissue        plasminogen activator (t-PA), streptokinase, reteplase and        urokinase or plasminogen-modulating substances causing increased        formation of plasmin;    -   anticoagulatory substances (anticoagulants), such as, for        example, heparin (UFH), low-molecular-weight heparins (NMH),        such as, for example, tinzaparin, certoparin, parnaparin,        nadroparin, ardeparin, enoxaparin, reviparin, dalteparin,        danaparoid, semuloparin (AVE 5026), adomiparin (M118) and        EP-42675/ORG42675,    -   direct thrombin inhibitors (DTI) such as, for example, Pradaxa        (dabigatran), atecegatran (AZD-0837), DP-4088 and SSR-182289A,    -   direct factor Xa inhibitors such as, for example, rivaroxaban,        apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663,        darexaban (YM-150), otamixaban (FXV-673/RPR-130673), letaxaban        (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran        (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux,    -   substances which inhibit the aggregation of platelets (platelet        aggregation inhibitors, thrombocyte aggregation inhibitors),        such as, for example, acetylsalicylic acid (such as, for        example, aspirin), P2Y12 antagonists such as, for example,        ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel,        ticagrelor, cangrelor, elinogrel, PAR-1 antagonists such as, for        example, vorapaxar, PAR-4 antagonists, EP3 antagonists such as,        for example, DG041;    -   platelet adhesion inhibitors such as GPVI and/or GPIb        antagonists such as, for example, Revacept or caplacizumab;    -   fibrinogen receptor antagonists (glycoprotein-IIb/IIIa        antagonists), such as, for example, abciximab, eptifibatide,        tirofiban, lamifiban, lefradafiban and fradafiban;    -   and also antiarrhythmics;    -   inhibitors of VEGF and/or PDGF signal paths such as, for        example, aflibercept, ranibizumab, bevacizumab, KH-902,        pegaptanib, ramucirumab, squalamin or bevasiranib, apatinib,        axitinib, brivanib, cediranib, dovitinib, lenvatinib, linifanib,        motesanib, pazopanib, regorafenib, sorafenib, sunitinib,        tivozanib, vandetanib, vatalanib, Vargatef and E-10030;    -   inhibitors of angiopoietin-Tie signal paths such as, for        example, AMG386;    -   inhibitors of Tie2 receptor tyrosine kinase;    -   inhibitors of the integrin signal paths such as, for example,        volociximab, cilengitide and ALG1001;    -   inhibitors of the PI3K-Akt-mTor signal paths such as, for        example, XL-147, perifosine, MK2206, sirolimus, temsirolimus and        everolimus;    -   corticosteroids such as, for example, anecortave, betamethasone,        dexamethasone, triamcinolone, fluocinolone and fluocinolone        acetonide;    -   inhibitors of the ALK1-Smad1/5 signal path such as, for example,        ACE041;    -   cyclooxygenase inhibitors such as, for example, bromfenac and        nepafenac;    -   inhibitors of the kallikrein-kinin system such as, for example,        safotibant and ecallantide;    -   inhibitors of the sphingosine 1-phosphate signal paths such as,        for example, sonepcizumab;    -   inhibitors of the complement-C5a receptor such as, for example,        eculizumab;    -   inhibitors of the 5HT1a receptor such as, for example,        tandospirone;    -   inhibitors of the Ras-Raf-Mek-Erk signal path; inhibitors of the        MAPK signal paths; inhibitors of the FGF signal paths;        inhibitors of endothelial cell proliferation; apoptosis-inducing        active compounds;    -   photodynamic therapy consisting of an active compound and the        action of light, the active compound being, for example,        verteporfin.

The compounds according to the invention may act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,extraocular, intraocular or otic route, or as an implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichfunction according to the prior art and deliver the compounds accordingto the invention rapidly and/or in modified fashion, and which containthe compounds according to the invention in crystalline and/oramorphized and/or dissolved form, for example tablets (uncoated orcoated tablets, for example having enteric coatings or coatings whichare insoluble or dissolve with a delay and control the release of thecompound according to the invention), tablets which disintegrate rapidlyin the mouth, or films/wafers, films/lyophilizates, capsules (forexample hard or soft gelatin capsules), sugar-coated tablets, granules,pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass an absorption step (e.g.intravenously, intraarterially, intracardially, intraspinally orintralumbally) or include an absorption (e.g. intramuscularly,subcutaneously, intracutaneously, percutaneously or intraperitoneally).Suitable administration forms for parenteral administration includeinjection and infusion formulations in the form of solutions,suspensions, emulsions, lyophilizates or sterile powders.

Suitable for extraocular (topic) administration are administration formswhich operate in accordance with the prior art, which release the activecompound rapidly and/or in a modified or controlled manner and whichcontain the active compound in crystalline and/or amorphized and/ordissolved form such as, for example, eye drops, sprays and lotions (e.g.solutions, suspensions, vesicular/colloidal systems, emulsions,aerosols), powders for eye drops, sprays and lotions (e.g. ground activecompound, mixtures, lyophilizates, precipitated active compound),semisolid eye preparations (e.g. hydrogels, in-situ hydrogels, creamsand ointments), eye inserts (solid and semisolid preparations, e.g.bioadhesives, films/wafers, tablets, contact lenses).

Intraocular administration includes, for example, intravitreal,subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar andsubtenon administration. Suitable for intraocular administration areadministration forms which operate in accordance with the prior art,which release the active compound rapidly and/or in a modified orcontrolled manner and which contain the active compound in crystallineand/or amorphized and/or dissolved form such as, for example,preparations for injection and concentrates for preparations forinjection (e.g. solutions, suspensions, vesicular/colloidal systems,emulsions), powders for preparations for injection (e.g. ground activecompound, mixtures, lyophilizates, precipitated active compound), gelsfor injection (semisolid preparations, e.g. hydrogels, in-situhydrogels) and implants (solid preparations, e.g. biodegradable andnonbiodegradable implants, implantable pumps).

Preference is given to oral administration or, in the case ofophthalmologic disorders, extraocular and intraocular administration.

Suitable administration forms for the other administration routes are,for example, pharmaceutical forms for inhalation (including powderinhalers, nebulizers), nasal drops, solutions or sprays; tablets forlingual, sublingual or buccal administration, films/wafers or capsules,suppositories, preparations for the ears or eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (for examplepatches), milk, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be converted to theadministration forms mentioned. This can be done in a manner known perse, by mixing with inert, nontoxic, pharmaceutically suitableexcipients. These auxiliaries include carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersing or wetting agents (forexample sodium dodecylsulphate, polyoxysorbitan oleate), binders (forexample polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants, for example ascorbicacid), dyes (e.g. inorganic pigments, for example iron oxides) andflavour and/or odour correctants.

The present invention further provides medicaments comprising at leastone compound according to the invention, preferably together with one ormore inert nontoxic pharmaceutically suitable excipients, and the usethereof for the purposes mentioned above.

In the case of parenteral administration, it has generally been found tobe advantageous to administer amounts of about 5 to 250 mg every 24hours to achieve effective results. In the case of oral administration,the amount is about 5 to 500 mg every 24 hours.

In spite of this, it may be necessary to deviate from the amountsspecified, specifically depending on body weight, administration route,individual behaviour towards the active compound, type of formulation,and time or interval of administration.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration figures forliquid/liquid solutions are each based on volume. “w/v” means“weight/volume”. For example, “10% w/v” means: 100 ml of solution orsuspension comprise 10 g of substance.

A) EXAMPLES Abbreviations

-   CDI carbonyldiimidazole-   d day(s), doublet (in NMR)-   DAD diode array detector-   TLC thin-layer chromatography-   DCM dichloromethane-   DCI direct chemical ionization (in MS)-   dd doublet of doublets (in NMR)-   DIC N,N′-diisopropylcarbodiimide-   DIEA N,N-diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF N,N-dimethylformamide-   DMSO dimethyl sulphoxide-   eq. equivalent(s)-   ESI electrospray ionization (in MS)-   h hour(s)-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC high-pressure, high-performance liquid chromatography-   HV high vacuum-   LC-MS liquid chromatography-coupled mass spectroscopy-   LDA lithium diisopropylamide-   m multiplet (in NMR)-   min minute(s)-   MS mass spectroscopy-   NMR nuclear magnetic resonance spectroscopy-   oxima ethyl hydroxyiminocyanoacetate-   quant. quantitative-   RP reversed phase (in HPLC)-   RT room temperature-   R_(t) retention time (in HPLC)-   s singlet (in NMR)-   SFC supercritical fluid chromatography (with supercritical carbon    dioxide as mobile phase)-   THF tetrahydrofuran-   TFA trifluoroacetic acid-   T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XPhos precatalyst [(2′-aminobiphenyl-2-yl)(chloro)palladium    dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane (1:1)], J.    Am. Chem. Soc. 2010, 132, 14073-14075    HPLC, LC/MS and GC Methods:    Method 1:

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 90% A→1.2 min 5% A→2.0 min 5% A;oven: 50° C.; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

Method 2:

Instrument: Waters ACQUITY SQD UPLC System; column: Waters Acquity UPLCHSS T3 1.8μ 50×1 mm; mobile phase A: 1 l of water+0.25 ml of 99%strength formic acid, mobile phase B: 1 l of acetonitrile+0.25 ml of 99%strength formic acid; gradient: 0.0 min 95% A→6.0 min 5% A→7.5 min 5% A;oven: 50° C.; flow rate: 0.35 ml/min; UV detection: 210-400 nm.

Method 3:

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50×1 mm; mobile phase A: 1 l of water+0.5 mlof 50% strength formic acid, mobile phase B: 1 l of acetonitrile+0.5 mlof 50% strength formic acid; gradient: 0.0 min 97% A→0.5 min 97% A→3.2min 5% A→4.0 min 5% A; oven: 50° C.; flow rate: 0.3 ml/min; UVdetection: 210 nm.

Method 4:

MS instrument: Waters (Micromass) Quattro Micro; HPLC instrument:Agilent 1100 series; column: YMC-Triart C18 3μ 50×3 mm; mobile phase A:1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1 l ofacetonitrile; gradient: 0.0 min 100% A→2.75 min 5% A→4.5 min 5% A; oven:40° C.; flow rate: 1.25 ml/min; UV detection: 210 nm.

Method 5:

MS instrument: Waters (Micromass) QM; HPLC instrument: Agilent 1100series; column: Agient ZORBAX Extend-C18 3.0×50 mm 3.5 micron; mobilephase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1l of acetonitrile; gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5%A→4.5 min 5% A; oven: 40° C.; flow rate: 1.75 ml/min; UV detection: 210nm.

Method 6:

MS instrument: Waters (Micromass) ZQ; HPLC instrument: Agilent 1100series; column: Agient ZORBAX Extend-C18 3.0×50 mm 3.5 micron; mobilephase A: 1 l of water+0.01 mol of ammonium carbonate, mobile phase B: 1l of acetonitrile; gradient: 0.0 min 98% A→0.2 min 98% A→3.0 min 5%A→4.5 min 5% A; oven: 40° C.; flow rate: 1.75 ml/min; UV detection: 210nm.

Method 7:

Instrument: Thermo DFS, Trace GC Ultra; column: Restek RTX-35, 15 m×200μm×0.33 μm; constant flow rate with helium: 1.20 ml/min; oven: 60° C.;inlet: 220° C.; gradient: 60° C., 30° C./min→300° C. (hold for 3.33min).

Method 8:

Instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; column: WatersAcquity UPLC HSS T3 1.8μ 50 mm×2.1 mm; mobile phase A: 1 l of water+0.25ml of 99% strength formic acid, mobile phase B: 1 l of acetonitrile+0.25ml of 99% strength formic acid; gradient: 0.0 min 90% A→0.3 min 90%A→1.7 min 5% A→3.0 min 5% A; oven: 50° C.; flow rate: 1.20 ml/min; UVdetection: 205-305 nm.

Method 9:

Instrument: Thermo Scientific DSQII, Thermo Scientific Trace GC Ultra;column: Restek RTX-35MS, 15 m×200 μm×0.33 μm; constant flow rate withhelium: 1.20 ml/min; oven: 60° C.; inlet: 220° C.; gradient: 60° C., 30°C./min→300° C. (hold for 3.33 min).

Method 10:

MS instrument: Waters SQD; HPLC instrument: Waters UPLC; column: ZorbaxSB-Aq (Agilent), 50 mm×2.1 mm, 1.8 μm; mobile phase A: water+0.025%formic acid, mobile phase B: acetonitrile (ULC)+0.025% formic acid;gradient: 0.0 min 98% A—0.9 min 25% A—1.0 min 5% A—1.4 min 5% A—1.41 min98% A—1.5 min 98% A; oven: 40° C.; flow rate: 0.600 ml/min; UVdetection: DAD; 210 nm.

Method 11:

MS instrument type: Waters Synapt G2S; UPLC instrument type: WatersAcquity I-CLASS; column: Waters, HSST3, 2.1 mm×50 mm, C18 1.8 μm; mobilephase A: 1 l of water+0.01% formic acid; mobile phase B: 1 l ofacetonitrile+0.01% formic acid; gradient: 0.0 min 10% B→0.3 min 10%B→1.7 min 95% B→2.5 min 95% B; oven: 50° C.; flow rate: 1.20 ml/min; UVdetection: 210 nm.

Microwave:

The microwave reactor used was a single-mode instrument of the Emrys™Optimizer type.

Starting Materials

General Method 1A: Preparation of a Boronic Acid

At −78° C., LDA (2 molar in THF/heptane/ethylbenzene) was added to asolution of the appropriate pyridine derivative in THF (3 ml/mmol), themixture was stirred for 2-4 h and triisopropyl borate was then addedquickly. The reaction mixture was maintained at −78° C. for a further2-3 h and then slowly thawed to RT overnight. After addition of water,the THF was removed under reduced pressure and the aqueous phase wasextracted twice with ethyl acetate The aqueous phase was acidified with2M hydrochloric acid, generally resulting in formation of a precipitatewhich was filtered off, washed with water and dried. The aqueous phasewas extracted three times with ethyl acetate. The combined organicphases were dried (sodium sulphate), filtered and concentrated underreduced pressure.

General Method 2A: Suzuki Coupling

In a flask which had been dried by heating and flushed with argon, 1.0eq. of the appropriate boronic acids, 1.0 eq. of the aryl bromide oraryl iodide, 3.0 eq. of potassium carbonate and 0.1 eq. of[1,1-bis-(diphenylphosphino)ferrocene]palladium(II)chloride/monodichloromethane adduct ortetrakis(triphenylphosphine)palladium(0) were initially charged. Theflask was then evacuated three times and in each case vented with argon.Dioxane (6 ml/mmol) was added, and the reaction mixture was stirred at110° C. for a number of hours until substantially complete conversionhad been achieved. The reaction mixture was then filtered through Celiteand the filtrate was concentrated under reduced pressure. Water wasadded to the residue. After addition of ethyl acetate and phaseseparation, the organic phase was washed once with water and once withsaturated aqueous sodium chloride solution, dried (magnesium sulphate),filtered and concentrated under reduced pressure. The crude product wasthen purified either by flash chromatography (silica gel 60, mobilephase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanolmixtures) or by preparative HPLC (Reprosil C18, water/acetonitrilegradient or water/methanol gradient).

General Method 2B: Suzuki Coupling

In a flask which had been dried by heating and flushed with argon, 1.0eq. of the appropriate boronic acids, 1.0 eq. of the aryl bromide oraryl iodide and 0.05 eq. of XPhos precatalyst[(2′-aminobiphenyl-2-yl)(chloro)palladium/dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphane(1:1)], J. Am. Chem. Soc. 2010, 132, 14073-14075] were initiallycharged. The flask was then evacuated three times and in each casevented with argon. THF (about 12 ml/mmol) which had been degassed in anultrasonic bath and 3.0 eq. of aqueous potassium phosphate solution (0.5molar) were added, and the reaction mixture was stirred at 60° C. Waterand ethyl acetate were then added to the reaction mixture. After phaseseparation, the aqueous phase was extracted once with ethyl acetate. Thecombined organic phases were dried (sodium sulphate), filtered andconcentrated under reduced pressure. The crude product was then purifiedeither by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or by preparative HPLC (Reprosil C18, water/acetonitrile gradient orwater/methanol gradient).

General Method 3A: Methoxypyridine Cleavage

20 eq. of pyridinium hydrochloride or pyridinium hydrobromide were addedto a solution of the appropriate methoxypyridine in DMF (12.5 ml/mmol)and the mixture was stirred at 100° C. for a number of hours to days,with further pyridinium hydrochloride or pyridinium hydrobromide beingadded, until substantially complete conversion had been achieved.Subsequently, the reaction solution was concentrated under reducedpressure and the residue was triturated with water. The precipitateformed was filtered off, washed with water and dried under reducedpressure.

General Method 4A: N-Alkylation of 2-Pyridinone Derivatives with theAppropriate 2-Bromo- or 2-Chloropropanoic Acid Derivatives

Under argon, a suspension of 1.0 eq. of the appropriate 2-pyridinonederivative, 2.0 eq. of magnesium di-tert-butoxide and 1.05 eq. ofpotassium tert-butoxide in THF (5-10 ml/mmol) was stirred at RT for10-20 min. The reaction mixture was cooled in an ice bath, and 1.5 eq.of the appropriate 2-bromo- or 2-chloropropanoic acid derivative wereadded. The reaction mixture was then stirred initially at RT for 2.5 hand then further at 35-90° C. overnight and then quenched with 6 Nhydrochloric acid. After addition of ethyl acetate and phase separation,the organic phase was washed once with water and once with saturatedaqueous sodium chloride solution, dried (magnesium sulphate), filteredand concentrated under reduced pressure. The crude product was thenpurified either by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or by preparative HPLC (Reprosil C18, water/acetonitrile gradient orwater/methanol gradient).

General Method 4B: N-Alkylation of 2-Pyridinone Derivatives with theAppropriate 2-Bromo- or 2-Chloropropanoic Ester Derivatives in thePresence of Potassium Carbonate

Under argon and at RT, 1.2 eq. of the appropriate 2-bromo- or2-chloropropanoic ester derivative and 1.5 eq. of potassium carbonatewere added to a solution of 1.0 eq. of the appropriate 2-pyridinonederivative in dimethylformamide (5-10 ml/mmol), and the mixture wasstirred at 100° C. After removal of the DMF and addition of water/ethylacetate and phase separation, the organic phase was washed with waterand with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was then purified either by flash chromatography (silica gel 60,mobile phase: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18,water/acetonitrile gradient or water/methanol gradient).

General Method 4C: N-Alkylation of 2-Pyridinone Derivatives with theAppropriate 2-Bromo- or 2-Chloropropanoic Ester Derivatives in thePresence of Sodium Hydride/Lithium Bromide

Under argon and at 0° C., 1.25 eq. of sodium hydride (60% in mineraloil) were added to a solution of 1.0 eq. of the appropriate 2-pyridinonederivative in dimethylformamide (5-10 ml/mmol), and the mixture wasstirred at 0° C. for 10-20 min 2.0 eq. of lithium bromide were thenadded, the reaction mixture was stirred at RT for 15 min, 1.25 eq. ofthe appropriate 2-bromo- or 2-chloropropanoic ester derivative wereadded and the mixture was stirred at 65° C. After removal of the DMF andaddition of water/ethyl acetate and phase separation, the organic phasewas washed with water, dried (sodium sulphate), filtered andconcentrated under reduced pressure. The crude product was then purifiedeither by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or by preparative HPLC (Reprosil C18, water/acetonitrile gradient orwater/methanol gradient).

General Method 4D: N-Alkylation of 2-Pyridinone Derivatives with theAppropriate 2-Bromo- or 2-Chloropropanoic Ester Derivatives in thePresence of Sodium Hydride

Under argon and at RT, the appropriate 2-pyridinone derivative was addedto a suspension of sodium hydride (1.2 eq.) in dimethylformamide (5-10ml/mmol). The reaction mixture was stirred at RT for 30-90 min and thencooled to 0° C., the appropriate 2-bromo- or 2-chloropropanoic esterderivative (1.2 eq.) was added and the mixture was stirred at RT for 2-5h. After addition of water and phase separation, the aqueous phase wasextracted with ethyl acetate. The combined organic phases were dried(sodium sulphate or magnesium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by normalphase chromatography (mobile phase: cyclohexane/ethyl acetate mixturesor dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 4E: N-Alkylation of 2-Pyridinone Derivatives with theAppropriate Triflates in the Presence of Sodium Hydride

Under argon and at RT, sodium hydride (1.1-1.5 eq.) was added to asolution of the appropriate 2-pyridinone derivative (1 eq.) intetrahydrofuran (0.05-0.2M), and the mixture was stirred for 30-90 min.The appropriate triflate (1.0-2.0 eq.) was then added neat or as asolution in THF. The resulting reaction mixture was stirred at RT foranother 1-5 h. Saturated aqueous ammonium chloride solution was added tothe reaction mixture. After phase separation, the aqueous phase wasextracted with ethyl acetate. The combined organic phases were dried(sodium sulphate or magnesium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by normalphase chromatography (mobile phase: cyclohexane/ethyl acetate mixturesor dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 5A: Amide Coupling Using HATU/DIEA

Under argon and at RT, the amine (1.1 eq.), N,N-diisopropylethylamine(2.2 eq.) and a solution of HATU (1.2 eq.) in a little DMF were added toa solution of the appropriate carboxylic acid (1.0 eq.) indimethylformamide (7-15 ml/mmol). The reaction mixture was stirred atRT. After addition of water/ethyl acetate and phase separation, theorganic phase was washed with water and with saturated aqueous sodiumchloride solution, dried (sodium sulphate), filtered and concentratedunder reduced pressure. The crude product was then purified either byflash chromatography (silica gel 60, mobile phase: cyclohexane/ethylacetate mixtures or dichloromethane/methanol mixtures) or by preparativeHPLC (Reprosil C18, water/acetonitrile gradient or water/methanolgradient).

General Method 5B: Amide Coupling Using OXIMA/DIC

N,N′-Diisopropylcarbodiimide (DIC) (1 eq.) was added dropwise to adegassed solution of the appropriate carboxylic acid (1 eq.), aniline (1eq.) and ethyl hydroxyiminocyanoacetate (Oxima) (1 eq.) indimethylformamide (0.1M), and the resulting reaction solution wasstirred at RT-40° C. for 8-24 h. The solvent was removed under reducedpressure. The residue was either admixed with water and the desiredproduct was filtered off or purified by normal phase chromatography(cyclohexane/ethyl acetate gradient) or preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 5C: Amide Coupling Using T3P/Pyridine

Under argon and at 0° C., propylphosphonic anhydride (T3P, 50% in ethylacetate, 4 eq.) was added dropwise to a solution of the carboxylic acid(1 eq.) and the appropriate amine (1.5 eq.) in pyridine (0.15-0.05 M).This mixture was heated to 90° C. and stirred at 90° C. for 1-20 h. Thereaction mixture was cooled to RT, and water and ethyl acetate wereadded. After phase separation, the aqueous phase was extracted withethyl acetate. The combined organic phases were washed with aqueousbuffer solution (pH 5), with saturated aqueous sodium bicarbonatesolution and with saturated aqueous sodium chloride solution, dried(sodium sulphate or magnesium sulphate), filtered and concentrated underreduced pressure. The crude product was then optionally purified eitherby normal phase chromatography (mobile phase: cyclohexane/ethyl acetatemixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 6A: Hydrolysis of a Tert-Butyl Ester Using TFA

At RT, 20 eq. of TFA were added to a solution of 1.0 eq. of theappropriate tert-butyl ester derivative in dichloromethane (about 7ml/mmol), and the mixture was stirred at RT for 1-8 h. The reactionmixture was then concentrated under reduced pressure and the residue wasco-evaporated repeatedly with dichloromethane and/or toluene and driedunder reduced pressure. The crude product was then optionally purifiedeither by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or by preparative HPLC (Reprosil C18, water/acetonitrile gradient orwater/methanol gradient).

General Method 6B: Hydrolysis of a Methyl/Ethyl or Tert-Butyl Ester withLithium Hydroxide

At RT, 3.0 eq. of lithium hydroxide were added to a solution of 1.0 eq.of the appropriate methyl or ethyl ester in tetrahydrofuran/water (3:1,about 10 ml/mmol). The reaction mixture was stirred at RT to 60° C. andthen adjusted to pH 1 using aqueous 1 N hydrochloric acid solution.After addition of water/ethyl acetate and phase separation, the aqueousphase was extracted three times with ethyl acetate. The combined organicphases were dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by flashchromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetatemixtures or dichloromethane/methanol mixtures) or by preparative HPLC(Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

General Method 6C: Hydrolysis of a Methyl or Ethyl Ester with CaesiumCarbonate

Caesium carbonate (2 eq.) was added to a solution of the appropriatemethyl or ethyl ester (1 eq.) in a mixture of methanol/water (4/1,0.05-0.2M), and the resulting suspension was stirred at RT-60° C. for3-8 h. The reaction mixture was then optionally cooled to RT andadjusted to pH 3 using aqueous hydrochloric acid (1N). Methanol wasremoved at 30° C. under reduced pressure. The aqueous phase wasextracted with ethyl acetate. The combined organic phases were dried(sodium sulphate or magnesium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by normalphase chromatography (mobile phase: cyclohexane/ethyl acetate mixturesor dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 7A: Alkylation of Acetic Esters with Halides

Under argon and at −78° C., 1.1 eq. of bis(trimethylsilyl)lithium amide(1.0M in THF) were added to a solution of the appropriate acetic esterin THF (about 10 ml/mmol), and the mixture was stirred at −78° C. for 10min. A solution of the appropriate iodide/bromide/chloride in THF wasthen added, and the reaction mixture was stirred at −78° C. for 10 minand further in an ice bath and then quenched with water. After additionof ethyl acetate and phase separation, the aqueous phase was extractedtwice with ethyl acetate. The combined organic phases were dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was then purified either by flash chromatography (silica gel 60,mobile phase: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18,water/acetonitrile gradient or water/methanol gradient).

General Method 7B: Alkylation of Acetic Esters with Triflates

Under argon and at −78° C., bis(trimethylsilyl)lithium amide (1.0M inTHF, 1.1-1.3 eq.) was added dropwise to a solution of the appropriateacetic ester (1 eq.) in tetrahydrofuran (0.1-0.2M), and the mixture wasstirred for 15 min. The appropriate alkyl triflate (1.5-2.0 eq.) wasthen added neat or as a solution in THF. The resulting reaction mixturewas stirred at −78° C. for another 15 min and at RT for another 1 h.Saturated aqueous ammonium chloride solution was added to the reactionmixture. After phase separation, the aqueous phase was extracted withethyl acetate. The combined organic phases were dried (sodium sulphateor magnesium sulphate), filtered and concentrated under reducedpressure. The crude product was then purified either by normal phasechromatography (mobile phase: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 8A: Preparation of Triflates

A solution of the appropriate alcohol (1 eq.) was initially charged indichloromethane (0.1M), and at −20° C. lutidine (1.1-1.5 eq.) ortriethylamine (1.1-1.5 eq.) and trifluoromethanesulphonic anhydride(1.05-1.5 eq.) were added in succession. The reaction mixture wasstirred at −20° C. for another 1 h and then diluted with triple theamount (based on the reaction volume) of methyl tert-butyl ether. Theorganic phase was washed three times with a 3:1 mixture of saturatedaqueous sodium chloride solution/1N hydrochloric acid and finally withsaturated aqueous sodium bicarbonate solution, dried (sodium sulphate ormagnesium sulphate) and filtered, and the solvent was removed underreduced pressure. The crude product was used for the next step withoutfurther purification.

General Method 9A: Nitro Reduction with Iron/Ammonium Chloride

10 eq. of ammonium chloride were dissolved in an ethanol/water mixture(2:1) (about 2M), the mixture was heated to 95° C. and the nitroarylcompound (1 eq.) was added. 3 eq. of iron powder were added in smallportions over a period of 1 h. The reaction mixture was then stirred at95° C. for 30 min, and the hot mixture was then filtered throughkieselguhr. The filter cake was washed with ethanol and the filtrate wasfreed from ethanol under reduced pressure. The aqueous phase thatremained was extracted three times with diethyl ether. The combinedorganic phases were washed with saturated aqueous sodium chloridesolution, dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by normalphase chromatography (mobile phase: cyclohexane/ethyl acetate mixturesor dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 10A: Preparation of Tert-Butyl Esters

A solution of the corresponding carboxylic acid (1 eq.) in toluene(0.15-0.05M) was heated to 60-100° C., and N,N-dimethylformamidedi-tert-butyl acetal (4 eq.) was added dropwise. The reaction mixturewas stirred at 60-100° C. for 1-5 h and cooled to RT, and ethyl acetatewas added. The organic phase was washed with saturated aqueous sodiumbicarbonate solution and with saturated aqueous sodium chloridesolution, dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was used for the next step withoutpurification.

Example 1.1A 4-Nitrobenzenecarboximidohydrazide

At 0° C., 5.2 ml (29.8 mmol, 3 eq.) of N,N-diisopropylethylamine and0.62 g (purity 80%, 9.92 mmol, 1.0 eq.) of hydrazine monohydrate wereadded to a solution of 2.0 g (9.92 mmol) of4-nitrobenzenecarboximidamide monohydrochloride in 20 ml of methanol,and the mixture was stirred at RT for 64 h. The reaction mixture wasthen added to 10% strength sodium chloride solution and, after additionof ethyl acetate and phase separation, was extracted twice with ethylacetate. The combined organic phases were dried over sodium sulphate,filtered and concentrated under reduced pressure. Yield: 1.7 g (93% oftheory)

LC/MS [Method 4]: R_(t)=1.77 min; MS (ESIpos): m/z=181 (M+H)⁺

Example 1.1B 5-(4-Nitrophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole

At 0° C., 1.95 g (9.3 mmol, 1 eq.) of trifluoroacetic anhydride wereadded to a solution of 1.7 g (9.3 mmol) of4-nitrobenzenecarboximidohydrazide in 50 ml of dichloromethane and themixture was stirred at RT, with 50 ml of acetonitrile being added after20 min to improve the solubility of the reaction mixture. The reactionmixture was stirred at 50° C. for 3 h and then concentrated underreduced pressure. The residue was coevaporated three times withdichloromethane and dried under reduced pressure. Yield: 2.7 g (quant.)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=259 (M+H)⁺

Example 1.1C 4-[3-(Trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline

8.9 g (39.7 mmol, 4 eq.) of tin(II) chloride dihydrate were added to asolution of 2.7 g (9.9 mmol) of5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole in 110 ml ofethanol, and the mixture was stirred at 70° C. for 1 h. The reactionmixture was poured into ice-water, and sodium bicarbonate was addedcarefully until a pH of 8 had been reached. The mixture was filteredthrough a filter layer and the residue was washed with ethyl acetate.After phase separation, the aqueous phase was washed twice with ethylacetate. The combined organic phases were washed with aqueous sodiumchloride solution, dried (magnesium sulphate), filtered and concentratedunder reduced pressure. Yield: 1.9 g (79% of theory)

LC/MS [Method 4]: R_(t)=1.66 min; MS (ESIpos): m/z=229 (M+H)⁺

Example 1.2A 4-(1H-Imidazol-2-yl)aniline

A solution of 95 mg (0.5 mmol) of 2-(4-nitrophenyl)-1H-imidazole in 3 mlof ethanol was hydrogenated in the presence of 20 mg of palladium (10%on activated carbon) at RT and standard pressure. The reaction mixturewas then filtered through Celite and the filtrate was concentrated underreduced pressure and dried. Yield: 91 mg (quant.)

LC/MS [Method 5]: R_(t)=1.06 min; MS (ESIpos): m/z=160 (M+H)⁺

Example 1.3A 5-(4-Nitrophenyl)-2-(trifluoromethyl)-1H-imidazole

324 mg (purity 85%, 2.5 mmol, 3 eq.) of 2,2,2-trifluoroethaneimidamidewere added to a suspension of 200 mg (0.82 mmol) of2-bromo-1-(4-nitrophenyl)ethanone and 500 mg of sodium sulphate in 10 mlof acetonitrile, and the mixture was treated in an ultrasonic bath for 1h and then stirred at RT. The sodium sulphate was then filtered off andthe filtrate was concentrated under reduced pressure. The residue waspurified by preparative HPLC (Reprosil C18, water/methanol gradient).Yield: 104 mg (49% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=258 (M+H)⁺

Example 1.3B 4-[2-(Trifluoromethyl)-1H-imidazol-5-yl]aniline

A solution of 104 mg (0.4 mmol) of5-(4-nitrophenyl)-2-(trifluoromethyl)-1H-imidazole in 10 ml of ethanolwas hydrogenated in the presence of 15 mg of palladium (10% on activatedcarbon) at RT and standard pressure. The reaction mixture was thenfiltered through Celite and the filtrate was concentrated under reducedpressure and dried. Yield: 98 mg (quant.)

LC/MS [Method 1]: R_(t)=0.47 min; MS (ESIpos): m/z=228 (M+H)⁺

Example 1.4A tert-Butyl5-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

At RT, 2.7 g (12.2 mmol, 1.0 eq.) of di-tert-butyl dicarbonate and 1.7ml (12.2 mmol, 1.0 eq.) of triethylamine were added to a solution of 2.5g (12.2 mmol) of 5-(4-nitrophenyl)-1,2-dihydro-3H-pyrazol-3-one in 50 mlof dichloromethane, and the mixture was stirred at RT for 4 h. Thereaction mixture was diluted with dichloromethane and water. After phaseseparation, the organic phase was dried (sodium sulphate), filtered andconcentrated under reduced pressure. The crude product was purified byflash chromatography (silica gel 60, mobile phase:dichloromethane/methanol mixtures). Yield: 2.23 g (58% of theory).

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=306 (M+H)⁺

Example 1.4B tert-Butyl5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate

A solution of 2.2 g (7.1 mmol) of tert-butyl5-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate in 100 mlof ethanol was hydrogenated in the presence of 253 mg of palladium (10%on activated carbon) at RT and standard pressure. The reaction mixturewas then filtered through Celite and the filtrate was concentrated underreduced pressure and dried. Yield: 1.99 g (purity 90%, 92% of theory)

LC/MS [Method 6]: R_(t)=2.06 min; MS (ESIpos): m/z=276 (M+H)⁺

Example 1.5A 3-(4-Aminophenyl)-1,2,4-oxadiazol-5(4H)-one

6.5 g (29 mmol, 4 eq.) of tin(II) chloride dihydrate were added to asolution of 1.5 g (7.2 mmol) of3-(4-nitrophenyl)-1,2,4-oxadiazol-5(4H)-one in 75 ml of ethanol, and themixture was stirred at 70° C. for 1 h. The reaction mixture was pouredinto ice-water, and sodium bicarbonate was added carefully until a pH of8 had been reached. The mixture was filtered through a filter layer andthe residue was washed with ethyl acetate. The combined filtrates wereconcentrated under reduced pressure. The residue was stirred withdichloromethane and methanol, treated in an ultrasonic bath for 10 minand then filtered. The filtrate was concentrated under reduced pressureand dried. Yield: 1.4 g (quant.)

LC/MS [Method 1]: R_(t)=0.44 min; MS (ESIpos): m/z=178 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.42 (d, 2H), 6.51 (d, 2H), 5.23 (s,2H), 4.13 (br. s, 1H).

Example 1.6A 1-Benzyl 2-tert-butyl 1-methylhydrazine-1,2-dicarboxylate

At RT, 20.6 g (94.6 mmol, 1.2 eq.) of di-tert.-butyl dicarbonate in 42ml of dichloromethane were added to a solution of 14.2 g (78.8 mmol) ofbenzyl 1-methylhydrazinecarboxylate in 100 ml of propan-2-ol, and themixture was stirred at RT for 24 h. The reaction mixture was dilutedwith dichloromethane and water. After phase separation, the organicphase was dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was purified by flash chromatography(silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures).Yield: 24.8 g (purity 80%, 90% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIneg): m/z=279 (M−H)⁻

Example 1.6B tert-Butyl 2-methylhydrazinecarboxylate

A solution of 24.8 g (70.8 mmol) of 1-benzyl 2-tert-butyl1-methylhydrazine-1,2-dicarboxylate in 500 ml of ethanol washydrogenated in the presence of 1.24 g of palladium (10% on activatedcarbon) at RT and standard pressure. The reaction mixture was thenfiltered through Celite and the filtrate was concentrated under reducedpressure and dried. Yield: 12.3 g (purity 48%, 57% of theory)

Example 1.6C tert-Butyl2-(2-fluoro-4-nitrobenzoyl)-2-methylhydrazinecarboxylate

Under argon and at RT, 17.1 g (53.4 mmol, 1.3 eq.) of(benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate and 21.4 ml(123.1 mol, 3.0 eq.) of N,N-diisopropylethylamine were added to asolution of 9.1 g (49.3 mmol, 1.2 eq.) of 2-fluoro-4-nitrobenzoic acidin 200 ml of DMF, and the mixture was stirred at RT for 20 min. Asolution of 12.5 g (purity 48%, 41 mmol) of tert-butyl2-methylhydrazinecarboxylate in 50 ml of DMF was added, and the reactionmixture was stirred at RT for 6 h. After removal of the DMF underreduced pressure and addition of water/ethyl acetate and phaseseparation, the organic phase was washed with 10% aqueous citric acidand with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel 60, mobilephase: cyclohexane/ethyl acetate mixtures). Yield: 8.35 g (65% oftheory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIneg): m/z=312 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.78 (s, 1H), 8.20 (d, 1H), 8.11 (d,1H), 7.59 (t, 1H), 3.13 (s, 3H), 1.24 (s, 9H).

Example 1.6D 2-Fluoro-N-methyl-4-nitrobenzohydrazide

A solution of 3.6 g (11.5 mmol) of tert-butyl2-(2-fluoro-4-nitrobenzoyl)-2-methylhydrazinecarboxylate in 57 ml of4-molar hydrochloric acid/dioxane solution was stirred at RT for 3 h.The reaction mixture was concentrated under reduced pressure and theresidue was taken up in ethyl acetate and washed with saturated aqueoussodium bicarbonate solution. The organic phase was dried (sodiumsulphate), filtered and concentrated under reduced pressure. Yield: 2.0g (81% of theory)

LC/MS [Method 1]: R_(t)=0.50 min; MS (ESIpos): m/z=214 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.09 (m, 2H), 7.61 (dd, 1H), 3.2 (s,3H).

Example 1.6E 2-Methyl-6-nitro-1,2-dihydro-3H-indazol-3-one

At RT, 6.6 ml (37.9 mmol, 3.5 eq.) of N,N-diisopropylethylamine wereadded to a solution of 2.4 g (10.9 mmol) of2-fluoro-N-methyl-4-nitrobenzohydrazide in 25 ml of DMF, and the mixturewas stirred at 80° C. overnight. The reaction mixture was concentratedunder reduced pressure and the residue was taken up in ethyl acetate.The precipitated solid was filtered off and dried under reducedpressure. Yield: 595 mg (28% of theory)

LC/MS [Method 1]: R_(t)=0.49 min; MS (ESIpos): m/z=194 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.14 (s, 1H), 7.85 (d, 1H), 7.78 (dd,1H), 3.48 (s. 3H).

Alternative Synthesis:

1.66 g (9.27 mmol) of 6-nitro-1,2-dihydro-3H-indazol-3-one wereinitially charged in 20 ml of DMF, and 1.75 ml (18.5 mmol, 2.0 eq.) ofdimethyl sulphate were added. The reaction mixture was heated at 60° C.for 8 h and then diluted with dichloromethane and shaken with saturatedaqueous sodium carbonate solution. The aqueous phase was washed threetimes each with dichloromethane and with ethyl acetate and the organicfractions were discarded. Using 4N aqueous hydrochloric acid, theaqueous phase was then carefully adjusted to pH 4.5 and extracted threetimes with ethyl acetate. These combined organic phases were dried overmagnesium sulphate and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel 50, mobilephase: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate/methanol15:1), giving the title compound. Yield: 770 mg (43% of theory)

LC/MS [Method 1]: R_(t)=0.50 min; MS (ESIpos): m/z=194 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.2 (br. s., 1H), 8.15 (d, 1H), 7.88(d, 1H), 7.82 (dd, 1H), 3.48 (s, 3H).

Example 1.6F tert-Butyl2-methyl-6-nitro-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate

At RT, a solution of 0.8 g (3.7 mmol, 1.2 eq.) of di-tert.-butyldicarbonate in 6 ml of dichloromethane was added to a solution of 595 mg(3.0 mmol) of 2-methyl-6-nitro-1,2-dihydro-3H-indazol-3-one in 25 ml ofpropan-2-ol, and the mixture was stirred at RT for 12 h. To improve thesolubility of the reaction mixture, 6 ml of DMF were added. A further 4eq. of di-tert-butyl dicarbonate were added, and the reaction mixturewas stirred at RT for 24 h and then diluted with dichloromethane andwater. After phase separation, the organic phase was dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel 60, mobilephase: cyclohexane/ethyl acetate mixtures). Yield: 720 mg (80% oftheory)

LC/MS [Method 1]: R_(t)=1.04 min; MS (ESIpos): m/z=194 (M+H-Boc)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.62 (d, 1H), 8.17 (dd, 1H), 8.05 (d,1H), 3.58 (s. 3H), 1.63 (s, 9H).

Example 1.6G tert-Butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate

A solution of 715 mg (2.4 mmol) of tert-butyl2-methyl-6-nitro-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate in 30 ml ofethanol was hydrogenated in the presence of 52 mg of palladium (10% onactivated carbon) at RT and standard pressure. The reaction mixture wasthen filtered through Celite and the filtrate was concentrated underreduced pressure and dried. Yield: 668 mg (100% of theory)

LC/MS [Method 1]: R_(t)=0.79 min; MS (ESIpos): m/z=264 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.36 (d, 1H), 6.94 (d, 1H), 6.53 (dd,1H), 6.21 (s, 2H), 1.58 (s, 9H).

Example 1.6H 6-Nitro-1,2-dihydro-3H-indazol-3-one

In two portions of equal size, a total of 2.00 g (10.0 mmol) of methyl2-fluoro-4-nitrobenzoate and 2.51 g (50.2 mmol) of hydrazine monohydratein 36 ml of ethanol were heated in a microwave reactor at 120° C. for 2h. The combined reaction solutions were diluted with ethyl acetate andwashed with water. The aqueous phase was extracted three times withethyl acetate. The combined organic phases were dried over magnesiumsulphate and concentrated under reduced pressure. Yield: 1.66 g (purity95%, 88% of theory)

LC/MS [Method 11]: R_(t)=0.73 min; MS (ESIpos): m/z=180 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.4 (s, 1H), 11.0 (br. s, 1H), 8.21(d, 1H), 7.86 (d, 1H), 7.78 (dd, 1H).

Example 1.7A 1,3-Thiazolidine-2,4-dione potassium salt

At 50° C., a solution of 1.05 g (18.8 mmol, 1.1 eq.) of potassiumhydroxide in 3 ml of ethanol was added to a solution of 2.0 g (17.1mmol) of 1,3-thiazolidine-2,4-dione in 7 ml of ethanol, and the mixturewas stirred at RT for 2 h. The precipitate formed was filtered off,washed with ethanol and dried under reduced pressure. Yield: 2.3 g (87%of theory)

Example 1.7B 3-[2-(4-Nitrophenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione

A little at a time, 1.3 g (8.4 mmol) of 1,3-thiazolidine-2,4-dionepotassium salt were added to a solution of 2.0 g (8.2 mmol) of2-bromo-1-(4-nitrophenyl)ethanone in 80 ml of acetone, and the mixturewas stirred at 60° C. for 1 h. The reaction mixture was concentratedunder reduced pressure and the residue was dissolved inwater/dichloromethane. After phase separation, the organic phase wasdried (sodium sulphate), filtered, concentrated under reduced pressureand dried. Yield: 2.3 g (98% of theory)

LC/MS [Method 3]: R_(t)=1.81 min; MS (ESIpos): m/z=281 (M+H)⁺.

Example 1.7C 5-(4-Nitrophenyl)-1,3-oxazol-2(3H)-one

2.8 ml (20.1 mmol, 2.5 eq.) of triethylamine were added to a solution of2.3 g (8.0 mmol) of3-[2-(4-nitrophenyl)-2-oxoethyl]-1,3-thiazolidine-2,4-dione in 80 ml ofethanol, and the mixture was stirred under reflux for 14 h. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in water/ethyl acetate. After phase separation, the organicphase was dried (sodium sulphate), filtered, concentrated under reducedpressure and dried. The residue was stirred in dichloromethane and theprecipitate was filtered off and dried under reduced pressure. Yield:1.1 g (67% of theory)

LC/MS [Method 1]: R_(t)=0.71 min; MS (ESIneg): m/z=205 (M−H)⁻.

Example 1.7D 5-(4-Aminophenyl)-1,3-oxazol-2(3H)-one

A solution of 1.1 g (5.4 mmol) of 5-(4-nitrophenyl)-1,3-oxazol-2(3H)-onein 40 ml of ethanol was hydrogenated in the presence of 111 mg ofpalladium (10% on activated carbon) at RT and standard pressure for 5 d.The reaction mixture was then filtered through Celite and the residuewas washed with ethanol. The combined filtrates were concentrated underreduced pressure. The residue was used for the next step without furtherpurification. Yield: 626 mg (purity 88%, 58% of theory)

LC/MS [Method 5]: R_(t)=1.23 min; MS (ESIpos): m/z=177 (M+H)⁺.

Example 1.8A 6-Nitro-2-(trichloromethyl)-1H-benzimidazole

At 0° C., 6.3 g (35.9 mmol, 1.1 eq.) of methyl2,2,2-trichloroethaneimidoate were added dropwise to a solution of 5.0 g(32.7 mmol) of 4-nitrobenzene-1,2-diamine in 150 ml of glacial aceticacid. The reaction mixture was stirred at RT for 3 h and then added to400 ml of water, and 300 ml of ethyl acetate were added. After phaseseparation, the aqueous phase was extracted twice with ethyl acetate.The combined organic phases were washed twice with in each case 130 mlof saturated aqueous sodium bicarbonate solution and once with saturatedaqueous sodium chloride solution, dried (sodium sulphate), filtered andconcentrated under reduced pressure and dried. The crude product wastriturated with pentane and left to stand overnight. The solid was thenfiltered off, washed with pentane and dried under reduced pressure.Yield: 10.1 g (purity 77%, 85% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=280 (M+H)⁺.

Example 1.8B Ethyl 6-nitro-1H-benzimidazole-2-carboxylate

15.4 g (90.7 mmol, 3.3 eq.) of silver(I) nitrate were added to asolution of 10.0 g (purity 77%, 27.5 mmol) of6-nitro-2-(trichloromethyl)-1H-benzimidazole in 100 ml of ethanol, andthe mixture was stirred under reflux for 15 h, cooled to RT andconcentrated under reduced pressure. The residue was taken up in amixture of 250 ml of hydrochloric acid (1N) and 220 ml of ethyl acetate,stirred for 1 h and filtered through silica gel. After phase separation,the organic phase was dried (sodium sulphate), filtered, concentratedunder reduced pressure and dried. The residue was triturated with 30 mlof diisopropyl ether, filtered off, washed with diisopropyl ether andpetroleum ether and dried under reduced pressure. Yield: 1.9 g (29% oftheory)

LC/MS [Method 1]: R_(t)=0.70 min; MS (ESIpos): m/z=236 (M+H)⁺.

Example 1.8C Ethyl 6-amino-1H-benzimidazole-2-carboxylate

A solution of 1.9 g (8.1 mmol) of ethyl6-nitro-1H-benzimidazole-2-carboxylate in 30 ml of ethanol washydrogenated in the presence of 190 mg of palladium (10% on activatedcarbon) at RT and standard pressure for 3 h. The reaction mixture wasthen filtered through kieselguhr and the residue was washed withethanol. The combined filtrates were concentrated under reducedpressure. The residue was dried under reduced pressure and then purifiedby flash chromatography (silica gel 50, mobile phase:dichloromethane/methanol 3-5%). Yield: 640 mg (39% of theory)

LC/MS [Method 5]: R_(t)=1.34 min; MS (ESIpos): m/z=206 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.71 (s, 1H), 7.38 (d, 1H), 6.63(dd, 1H), 6.58 (s, 1H), 5.29 (s, 2H), 4.34 (q, 2H), 1.34 (t, 3H).

Example 1.9A 5-Amino-3-chloro-1H-indazole

1.00 g (5.06 mmol) of 3-chloro-5-nitro-1H-indazole was suspended in 50ml of ethanol, and 5.71 g (25.3 mmol) of tin(II) chloride dihydrate wereadded. The mixture was left to stir at reflux overnight, saturatedaqueous sodium bicarbonate solution was then added and the mixture wasextracted three times with ethyl acetate. The combined organic phaseswere dried over magnesium sulphate and the solvent was removed underreduced pressure. The mixture was triturated with tert-butyl methylether and the solid was filtered off with suction. Yield: 544 mg (purity90%, 58% of theory)

LC/MS [Method 5]: R_(t)=1.50 min; MS (ESIpos): m/z=168 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 7.28 (d, 1H), 6.89 (dd,1H), 6.66 (m, 1H), 5.46 (br. s, 2H).

Example 1.10A tert-Butyl 2-fluoro-4-nitrobenzoate

At 0° C., 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added to asolution of 500 mg (2.7 mmol) of 2-fluoro-4-nitrobenzoic acid and 1.03 g(5.4 mmol, 2.0 eq.) of para-toluenesulphonyl chloride in 5.4 ml ofpyridine, the mixture was stirred for 60 min and a further 0.258 ml (2.7mmol, 1.0 eq.) of tert-butanol was added. The reaction mixture wasstirred for another 18 h and concentrated under reduced pressure.Saturated aqueous sodium bicarbonate solution and ethyl acetate wereadded to the residue. After phase separation, the aqueous phase wasextracted with ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was then purified by normal phase chromatography (mobile phase:cyclohexane/ethyl acetate 14%-20% mixtures). Yield: 524 mg (75% oftheory).

LC/MS [Method 1]: R_(t)=1.16 min; MS (ESIneg): m/z=226 (M-CH₃)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.21 (dd, 1H), 8.16-8.12 (m, 1H),8.06 (dd, 1H), 1.56 (s, 9H).

Example 1.10B tert-Butyl 4-amino-2-fluorobenzoate

A solution of 1.109 g (20.73 mmol, 10 eq.) of ammonium chloride in 6.25ml of ethanol and 3.125 ml of water was heated to 95° C., and 500 mg(2.07 mmol) of tert-butyl 2-fluoro-4-nitrobenzoate were added. 347 mg(6.22 mmol, 3 eq.) of iron powder were added in small portions over 1 h.The reaction mixture was then stirred at 95° C. for 30 min, and the hotmixture was then filtered through kieselguhr. The filter cake was washedwith ethanol and the filtrate was freed from ethanol under reducedpressure. The aqueous phase was extracted three times with in each case20 ml of diethyl ether. The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried (sodium sulphate),filtered and concentrated under reduced pressure. The crude product waspurified by normal phase chromatography (mobile phase: cyclohexane/ethylacetate 30%-50% mixtures). Yield: 280 mg (51% of theory).

LC/MS [Method 8]: R_(t)=1.18 min; MS (ESIneg): m/z=210 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.49 (t, 1H), 6.36 (dd, 1H), 6.25(dd, 1H), 6.15 (s, 2H), 1.48 (s, 9H).

Example 1.11A tert-Butyl 4-amino-3-fluorobenzoate

400 mg (1.66 mmol) of tert-butyl 3-fluoro-4-nitrobenzoate were reactedaccording to General Method 9A. The crude product was purified by normalphase chromatography (mobile phase: cyclohexane/ethyl acetate 15%-20%mixtures). Yield: 295 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=212 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.48-7.38 (m, 2H), 6.75 (t, 1H), 5.95(br. s, 2H), 1.50 (s, 9H).

Example 1.12A tert-Butyl 2,5-difluoro-4-nitrobenzoate

700 mg (3.45 mmol) of 2,5-difluoro-4-nitrobenzoate were reactedaccording to General Method 10A. The crude product was used for the nextstep without further purification. Yield: 1000 mg (purity 73%, 82% oftheory)

HPLC [Method 3]: R_(t)=2.45 min,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.24 (dd, 1H), 7.99 (dd, 1H), 1.56(s, 9H).

Example 1.12B tert-Butyl 4-amino-2,5-difluorobenzoate

A solution of 1000 mg (2.82 mmol) of tert-butyl2,5-difluoro-4-nitrobenzoate in 8 ml of tetrahydrofuran and 8 ml ofethyl acetate was hydrogenated in the presence of 65.6 mg of palladium(10% on activated carbon) at RT and standard pressure. The reactionmixture was then filtered through Celite and the filtrate wasconcentrated under reduced pressure and dried. The crude product waspurified by normal phase chromatography (mobile phase: cyclohexane/ethylacetate 15%-20% mixtures). Yield: 155 mg (purity 85%, 20% of theory)

LC/MS [Method 8]: R_(t)=1.27 min; MS (ESIpos): m/z=230 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.35 (dd, 1H), 6.47 (dd, 1H), 6.27(s, 2H), 1.49 (s, 9H).

Example 1.13A Methyl 4-[(tert-butoxycarbonyl)amino]-2,6-difluorobenzoate

Under argon, a microwave vessel was charged with 54 mg (0.22 mmol) ofmethyl 4-bromo-2,6-difluorobenzoate, 118 mg (1.01 mmol, 4.7 eq.) oftert-butyl carbamate, 4.6 mg (0.02 mmol, 0.1 eq.) of palladium(II)acetate, 15 mg (0.026 mmol, 0.13 eq.) of Xantphos, 137 mg (0.42 mmol, 2eq.) of caesium carbonate and 2 ml of 1,4-dioxane. A stream of argon waspassed through the suspension for 2 min. The reaction mixture was heatedin the microwave at 140° C. for 20 min. After filtration throughkieselguhr, the filtrate was concentrated under reduced pressure. Thecrude product was purified by normal phase chromatography (mobile phase:dichloromethane/methanol 10-50% mixtures). Yield: 37 mg (60% of theory)

LC/MS [Method 8]: R_(t)=1.35 min; MS (ESIneg): m/z=286 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.10 (s, 1H), 7.28-7.22 (m, 2H),3.83 (s, 3H), 1.49 (s, 9H).

Example 1.13B Methyl 4-amino-2,6-difluorobenzoate

At RT, 0.5 ml of TFA was added to a solution of 36 mg (0.125 mmol) ofmethyl 4-[(tert-butoxycarbonyl)amino]-2,6-difluorobenzoate in 1 ml ofdichloromethane, and the mixture was stirred at RT for 30 min. Thereaction mixture was then concentrated under reduced pressure and theresidue was co-evaporated repeatedly with dichloromethane and tolueneand dried under reduced pressure. The crude product was used for thenext step without purification. Yield: 24 mg (quant.)

LC/MS [Method 3]: R_(t)=1.56 min; MS (ESIpos): m/z=188 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=6.44 (s, 2H), 6.24-6.15 (m, 2H), 3.73(s, 3H).

Example 1.14A tert-Butyl [4-(N′-hydroxycarbamimidoyl)phenyl]carbamate

At RT, 1.40 g (20.16 mmol, 2.2 eq.) of hydroxylammonium chloride and2.81 ml (20.16 mmol, 2.2 eq.) of triethylamine were added to a solutionof 2.0 g (9.16 mmol) of tert-butyl-(4-cyanophenyl)carbamate in 45 ml ofethanol. The reaction mixture was heated under reflux for 4 h andconcentrated under reduced pressure. The residue was stirred with 100 mlof water at RT for 1 h. The reaction mixture was filtered and the filtercake was washed with water. The residue was dissolved in ethyl acetate.The aqueous phase that remained was separated off and the organic phasewas dried (sodium sulphate), filtered and concentrated under reducedpressure. The crude product was used for the next step withoutpurification. Yield: 2.10 g (purity 95%, 87% of theory)

LC/MS [Method 8]: Rt=0.68 min; MS (ESIpos): m/z=252 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.45 (s, 1H), 9.42 (br. s, 1H),7.57-7.52 (m, 2H), 7.46-7.40 (m, 2H), 5.69 (s, 2H), 1.48 (s, 9H).

Example 1.14B tert-Butyl[4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]carbamate

At RT, 560 mg (2.98 mmol, 1.5 eq.) of 1,1′-thiocarbonylimidazole wereadded to a solution of 500 mg (1.99 mmol) of tert-butyl[4-(N′-hydroxycarbamimidoyl)phenyl]carbamate in 16 ml oftetrahydrofuran, and the mixture was stirred at RT for 30 min. Water wasthen added to the reaction mixture. After phase separation, the aqueousphase was extracted with ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The residuewas dissolved in 8 ml of tetrahydrofuran, and 0.76 ml (5.97 mmol, 3.0eq.) of boron trifluoride/diethyl ether complex was added. The reactionmixture was stirred at RT for 1 h. After addition of water/ethyl acetateand phase separation, the aqueous phase was extracted three times withethyl acetate. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried (sodium sulphate), filtered andconcentrated under reduced pressure. The crude product was used for thenext step without purification. Yield: 130 mg (purity 70%, 15% oftheory)

LC/MS [Method 8]: Rt=1.18 min; MS (ESIpos): m/z=294 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.24 (br. s, 1H), 9.70 (s, 1H),7.87-7.80 (m, 2H), 7.61-7.54 (m, 2H), 1.49 (s, 9H).

Example 1.14C 3-(4-Aminophenyl)-1,2,4-thiadiazol-5(4H)-one

At 0° C., 0.8 ml of TFA was added to a solution of 129 mg (purity 70%,0.44 mmol) of tert-butyl[4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]carbamate in 4 ml ofdichloromethane, and the mixture was stirred at RT for 40 minSubsequently, the reaction mixture was concentrated under reducedpressure and the crude product was purified by preparative HPLC(water/acetonitrile/0.1% formic acid gradient). Yield: 54 mg (purity90%, 57% of theory)

LC/MS [Method 8]: Rt=0.68 min; MS (ESIpos): m/z=194 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.93 (br. s, 1H), 7.65-7.60 (m, 2H),6.64-6.58 (m, 2H), 5.58 (br. s, 2H).

Example 1.15A tert-Butyl[4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]carbamate

At RT, 821 mg (4.37 mmol, 2.2 eq.) of 1,1′-thiocarbonylimidazole and1.19 ml (7.96 mmol, 4.0 eq.) of 1,8-diazabicyclo[5.4.0]undec-7-ene wereadded to a solution of 500 mg (1.99 mmol) of tert-butyl[4-(N′-hydroxycarbamimidoyl)phenyl]carbamate in 20 ml of acetonitrile,and the mixture was stirred at RT for 24 h. The reaction mixture wasthen concentrated under reduced pressure and the residue was dissolvedin ethyl acetate. The organic phase was washed with water and apotassium citrate/citric acid solution (pH 5). The organic phase wasthen washed with a saturated aqueous sodium chloride solution, dried(sodium sulphate), filtered and concentrated under reduced pressure. Thecrude product was purified by normal phase chromatography (mobile phase:dichloromethane/methanol 0-10% mixtures). Yield: 120 mg (20% of theory)

LC/MS [Method 8]: Rt=1.17 min; MS (ESIneg): m/z=292 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.80 (s, 1H), 7.81-7.76 (m, 2H),7.67-7.62 (m, 2H), 1.49 (s, 9H).

Example 1.15B 3-(4-Aminophenyl)-1,2,4-oxadiazole-5(4H)-thione

At 0° C., 0.8 ml of TFA was added to a solution of 119 mg (0.40 mmol) oftert-butyl[4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]carbamate in 4 mlof dichlormethane, and the mixture was stirred at RT for 40 min.Subsequently, the reaction mixture was concentrated under reducedpressure. Ethyl acetate and a saturated aqueous sodium bicarbonatesolution were added to the residue. After phase separation, the aqueousphase was extracted with ethyl acetate. The aqueous phase wasconcentrated and the crude product was purified by preparative HPLC(water/acetonitrile/0.1% formic acid gradient). Yield: 30 mg (38% oftheory)

LC/MS [Method 8]: Rt=0.71 min; MS (ESIpos): m/z=194 (M+H)⁺.

Example 1.16A 4-(1,3-Oxazol-2-yl)aniline

250 mg (1.31 mmol) of 2-(4-nitrophenyl)-1,3-oxazole were reactedaccording to General Method 9A. The crude product was used for the nextstep without purification. Yield: 220 mg (99% of theory)

LC/MS [Method 1]: Rt=0.55 min; MS (ESIpos): m/z=161 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (d, 1H), 7.66-7.60 (m, 2H), 7.20(d, 1H), 6.66-6.59 (m, 2H), 5.67 (br. s, 2H).

Example 1.17A Methyl3-[5-(4-aminophenyl)-4H-1,2,4-triazol-3-yl]-2,2,3,3-tetrafluoropropanoate

A mixture of 9.7 g (48.5 mmol) of 4-nitrobenzenecarboximidohydrazide in150 ml of dichloromethane was stirred with 15.0 g (87.2 mmol) of3,3,4,4-tetrafluorodihydrofuran-2,5-dione at RT for 2 min, 150 ml ofacetonitrile were added to the suspension and the resulting solution wasstirred at RT for 16 h. The reaction mixture was adsorbed on silica geland separated by flash chromatography (dichloromethane/methanolmixtures). The product-containing fractions were combined andconcentrated under reduced pressure. The residue was stirred with alittle methanol, filtered and dried under reduced pressure.

The residue was dissolved in methanol, 1 ml of sulphuric acid was addedand the mixture was stirred at 70° C. for 4 h. Methanol was removed fromthe reaction mixture under reduced pressure. The residue was taken up inethyl acetate and extracted with saturated sodium bicarbonate solution.The organic phase was washed with a saturated sodium chloride solution,dried (sodium sulphate), filtered and concentrated under reducedpressure.

The residue was dissolved in 150 ml of ethanol, 43.2 g (191.8 mmol) oftin(II) chloride dihydrate were added and the mixture was stirred at 70°C. for 1 h. The reaction mixture was poured into ice-water, adjusted topH 8 with solid sodium bicarbonate and filtered through kieselguhr toremove the precipitated salts. The filtrate was extracted with ethylacetate. The combined organic phases were washed with saturated sodiumchloride solution, dried (sodium sulphate), filtered and concentratedunder reduced pressure. The residue was taken up in 600 ml of methanol,200 mg of sodium methoxide were added, and the mixture was stirred at RTfor 2 d. The reaction mixture was concentrated under reduced pressureand dried. Yield: 9.2 g (purity 91%, 99% of theory)

LC-MS (Method 1): R_(t)=0.77 min; MS (ESIpos): m/z=319 [M+H]⁺.

Example 2.1A tert-Butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate(racemate)

6.0 g (34.5 mmol) of 4-bromopyridin-2(1H)-one and 7.9 g (37.9 mmol) oftert-butyl 2-bromopropanoate (racemate) were reacted according toGeneral Method 4B. After removal of the DMF, the desired product wasprecipitated with water and then purified further by flashchromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetatemixtures). Yield: 7.4 g (69% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=302 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.66 (d, 1H), 6.75 (d, 1H), 6.51 (dd,1H), 5.04 (q, 1H), 1.51 (d, 3H), 1.37 (s, 9H).

Example 2.2A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate(racemate)

2.4 g (purity 74%, 5.9 mmol) of tert-butyl2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.2 g (6.8mmol) of 5-chloro-2-cyanophenylboronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 1.86 g (purity 87%, 77% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=359 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.03 (d, 1H), 7.84 (d, 1H), 7.81 (d,1H), 7.75 (dd, 1H), 6.64 (d, 1H), 6.50 (dd, 1H), 5.14 (q, 1H), 1.58 (d,3H), 1.40 (s, 9H).

Example 2.2B2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate)

2.2 g (purity 82%, 5.0 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 1.5 g (94% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=303 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.04 (br. s, 1H), 8.04 (d, 1H), 7.88(d, 1H), 7.82 (d, 1H), 7.76 (dd, 1H), 6.65 (d, 1H), 6.51 (dd, 1H), 5.23(q, 1H), 1.60 (d, 3H).

Example 2.2C tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

76 mg (purity 83%, 0.21 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 43 mg (43% of theory)

LC/MS [Method 1]: R_(t)=1.20 min; MS (ESIpos): m/z=478 (M+H)⁺

Example 2.3A tert-Butyl5-[4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate)

120 mg (purity 93%, 0.37 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of tert-butyl5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate werereacted according to General Method 5A. Yield: 110 mg (53% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=560 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.95 (s, 1H), 10.61 (s, 1H), 8.05(d, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.70 (m, 4H), 6.67(d, 1H), 6.56 (dd, 1H), 6.49 (d, 1H), 5.59 (q, 1H), 1.70 (d, 3H), 1.50(s, 9H).

Example 2.4A Methyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzoate(racemate)

120 mg (0.39 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of methyl 4-amino-2-fluorobenzoate were reactedaccording to General Method 5A. Yield: 64 mg (36% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=454 (M+H)⁺

Example 2.5A Methyl2-chloro-4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

120 mg (0.39 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of methyl 4-amino-2-chlorobenzoate were reactedaccording to General Method 5A. Following aqueous work-up, the desiredproduct was precipitated using a mixture of a little water, acetonitrileand DMF. Yield: 69 mg (38% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=470 (M+H)⁺

Example 2.6A Methyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methylbenzoate(racemate)

120 mg (0.39 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of methyl 4-amino-2-methylbenzoate were reactedaccording to General Method 5A. Following aqueous work-up, the desiredproduct was precipitated using a mixture of a little water, acetonitrileand DMF. Yield: 120 mg (69% of theory)

LC/MS [Method 1]: R_(t)=1.06 min; MS (ESIpos): m/z=450 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.69 (s, 1H), 8.04 (d, 1H), 7.94 (d,1H), 7.85 (d, 1H), 7.82 (d, 1H), 7.77 (dd, 1H), 7.57 (m, 2H), 6.66 (d,1H), 6.56 (dd, 1H), 5.56 (q, 1H), 3.8 (s, 3H), 1.69 (d, 3H).

Example 2.7A tert-Butyl6-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate)

89 mg (purity 83%, 0.24 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.1 eq. of tert-butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate werereacted according to General Method 5A. The crude product was purifiedby preparative HPLC (Reprosil C18, water/methanol gradient). Yield: 75mg (56% of theory)

LC/MS [Method 1]: R_(t)=1.04 min; MS (ESIpos): m/z=548 (M+H)⁺

Example 2.8A [(2-Bromo-4-chlorophenyl)ethynyl](trimethyl)silane

Under argon, 2.89 ml (20.7 mmol, 5.0 eq.) of triethylamine, 2.99 g (4.1mmol) of 2-bromo-4-chloro-1-iodobenzene and 489 mg (4.97 mmol, 1.2 eq.)of ethynyl(trimethyl)silane were added successively to a solution of 73mg (0.10 mmol, 0.025 eq.) of bis(triphenylphosphine)palladium(II)chloride and 20 mg (0.10 mmol, 0.025 eq.) copper(I) iodide in 27 ml ofTHF, and the mixture was stirred at RT overnight. The reaction mixturewas then diluted with ethyl acetate and filtered through Celite, and thefiltrate was concentrated under reduced pressure. After addition ofethyl acetate/water and phase separation, the organic phase wasconcentrated under reduced pressure. The crude product was purified byflash chromatography (silica gel 60, mobile phase: cyclohexane/ethylacetate mixtures). Yield: 3.21 g (quant.)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.70 (d, 1H), 7.40 (d, 1H), 7.29 (dd,1H), 0.07 (s, 9H).

Example 2.8B4-{5-Chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-methoxypyridine

A solution of 333 mg (1.16 mmol) of[(2-bromo-4-chlorophenyl)ethynyl](trimethyl)silane, 195 mg (1.28 mmol,1.1 eq.) of (2-methoxypyridin-4-yl)boronic acid, 401 mg (2.9 mmol, 2.5eq.) of potassium carbonate and 14 mg (0.02 mmol, 0.015 eq.) of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/monodichloromethane adduct in 18 ml of dioxane was irradiatedin a microwave at 130° C. for 15 min. The reaction mixture was thenfiltered through Celite and the residue was washed with dioxane. Thecombined filtrates were concentrated under reduced pressure. Afteraddition of water/ethyl acetate and phase separation, the organic phasewas concentrated under reduced pressure. Yield: 550 mg (purity 41%, 62%of theory)

LC/MS [Method 1]: R_(t)=1.50 min; MS (ESIpos): m/z=316 (M+H)⁺

Example 2.8C4-{5-Chloro-2-[(trimethylsilyl)ethynyl]phenyl}pyridin-2(1H)-one

550 mg (purity 41%, 0.71 mmol) of4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-methoxypyridine and 20eq. of pyridinium hydrochloride were reacted according to General Method3A. The reaction mixture was concentrated under reduced pressure andwater was added to the residue. After addition of ethyl acetate andphase separation, the organic phase was washed once with water, dried(sodium sulphate), filtered and concentrated under reduced pressure. Thecrude product was purified by flash chromatography (silica gel 60,cyclohexane/ethyl acetate and dichloromethane/methanol mixtures). Yield:141 mg (purity 91%, 59% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIpos): m/z=302 (M+H)⁺

Example 2.8D tert-Butyl2-[4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-oxopyridin-1(2H)-yl]propanoate

125 mg (purity 91%, 0.38 mmol) of4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}pyridin-2(1H)-one and 1.2eq. of tert-butyl 2-bromopropanoate (racemate) were reacted at 80° C.according to General Method 4B. Yield: 56 mg (purity 89%, 31% of theory)

LC/MS [Method 1]: R_(t)=1.42 min; MS (ESIpos): m/z=430 (M+H)⁺

Example 2.8E2-[4-(5-Chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate)

55 mg (purity 89%, 0.11 mmol) of tert-butyl2-[4-{5-chloro-2-[(trimethylsilyl)ethynyl]phenyl}-2-oxopyridin-1(2H)-yl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 50 mg (purity 82%, quant.)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=301 (M+H)⁺

Example 2.8F Methyl4-({2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate

50 mg (purity 82%, 0.32 mmol) of2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.2 eq. of methyl 4-aminobenzoate were reacted accordingto General Method 5A. Yield: 15 mg (25% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIpos): m/z=435 (M+H)⁺

Example 2.9A tert-Butyl2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate)

2.5 g (8.0 mmol) of tert-butyl2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.76 g (9.2mmol) of 2,5-dichlorophenylboronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 2.3 g (77% of theory)

LC/MS [Method 1]: R_(t)=1.20 min; MS (ESIpos): m/z=368 (M+H)⁺

Example 2.9B 2-[4-(2,5-Dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

A solution of 2.3 g (6.2 mmol) of tert-butyl2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate (racemate) ina 4-molar hydrochloric acid/dioxane solution was stirred at RT for 7 hand then concentrated under reduced pressure. The residue wascoevaporated three times with dichloromethane and dried under reducedpressure. Yield: 2.0 g (99% of theory)

LC/MS [Method 1]: R_(t)=0.88 min; MS (ESIpos): m/z=312 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.03 (br. s, 1H), 7.78 (d, 1H), 7.63(d, 1H), 7.57 (d, 1H), 7.54 (dd, 1H), 6.46 (d, 1H), 6.36 (dd, 1H), 5.21(q, 1H), 1.58 (d, 3H).

Example 2.9C tert-Butyl4-({2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

117 mg (0.36 mmol) of2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 83 mg (47% of theory)

LC/MS [Method 1]: R_(t)=1.32 min; MS (ESIpos): m/z=487 (M+H)⁺

Example 2.10A tert-Butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate(racemate)

856 mg (2.75 mmol) of tert-butyl2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 776 mg (3.3mmol) of 2-bromo-5-chlorophenylboronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 921 mg (80% of theory)

LC/MS [Method 1]: R_(t)=1.21 min; MS (ESIpos): m/z=412 (M+H)⁺

Example 2.10B2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate)

920 mg (2.2 mmol) of tert-butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 1110 mg (purity 93%, quant.)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=356 (M+H)⁺

Example 2.10C tert-Butyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

153 mg (purity 93%, 0.4 mmol) of2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 96 mg (44% of theory)

LC/MS [Method 1]: R_(t)=1.32 min; MS (ESIpos): m/z=531 (M+H)⁺

Example 2.11A tert-Butyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoate(racemate)

2.0 g (6.4 mmol) of tert-butyl2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.7 g (7.7mmol) of 5-chloro-2-(trifluoromethyl)phenylboronic acid in the presenceof tetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 2.3 g (purity 91%, 82% of theory)

LC/MS [Method 1]: R_(t)=1.22 min; MS (ESIpos): m/z=402 (M+H)⁺

Example 2.11B2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate)

2.3 g (purity 91%, 5.2 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 2.6 g (purity 93%, quant.)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=346 (M+H)⁺

Example 2.11C tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

130 mg (purity 93%, 0.35 mmol) of2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. The crude product was purified bypreparative HPLC (Reprosil C18, water/methanol gradient). Yield: 104 mg(56% of theory)

LC/MS [Method 1]: R_(t)=1.33 min; MS (ESIpos): m/z=521 (M+H)⁺

Example 3.1A tert-Butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)butanoate(racemate)

348 mg (2.0 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl2-bromobutanoate (racemate) were reacted according to General Method 4Bat 120° C. After aqueous work-up, the desired product was reactedfurther as crude product. Yield: 608 mg (purity 82%, 79% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=316 (M+H)⁺

Example 3.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoate (racemate)

600 mg (purity 82%, 1.56 mmol) of tert-butyl2-(4-bromo-2-oxopyridin-1(2H)-yl)butanoate (racemate) and 325 mg (1.8mmol) of 5-chloro-2-cyanophenylboronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 543 mg (purity 59%, 55% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=373 (M+H)⁺

Example 3.1C2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoic acid(racemate)

543 mg (purity 59%, 0.86 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoate (racemate)were hydrolysed with 20 eq. of TFA according to General Method 6A.Yield: 425 mg (purity 60%, 94% of theory)

LC/MS [Method 1]: R_(t)=0.78 min; MS (ESIpos): m/z=317 (M+H)⁺

Example 4.1A Ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-methylbutanoate(racemate)

500 mg (2.9 mmol) of 4-bromopyridin-2(1H)-one and 841 mg (4.02 mmol) ofethyl 2-bromo-3-methylbutanoate (racemate) in the presence of 1.15 eq.of sodium hydride and 2.3 eq. of lithium bromide were reacted accordingto General Method 4C. Yield: 260 mg (purity 92%, 28% of theory)

LC/MS [Method 3]: R_(t)=2.05 min; MS (ESIpos): m/z=302 (M+H)⁺

Example 4.1B Ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoate(racemate)

240 mg (purity 92%, 0.73 mmol) of ethyl2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-methylbutanoate (racemate) and 172mg (0.95 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/monodichloromethane adduct were reacted according to GeneralMethod 2A. Yield: 117 mg (purity 81%, 36% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=359 (M+H)⁺

Example 4.1C2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate)

117 mg (purity 81%, 0.26 mmol) of ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 79 mg (purity 86%, 78% of theory)

LC/MS [Method 1]: Rt=0.89 min; MS (ESIpos): m/z=331 (M+H)⁺

Example 5.1A Ethyl 2-(4-iodo-2-oxopyridin-1(2H)-yl)hexanoate (racemate)

500 mg (2.3 mmol) of 4-iodopyridin-2(1H)-one and 706 mg (3.2 mmol) ofethyl 2-bromohexanoate (racemate) in the presence of 1.15 eq. of sodiumhydride and 2.3 eq. of lithium bromide were reacted according to GeneralMethod 4C. Yield: 352 mg (43% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=364 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.45 (d, 1H), 6.96 (d, 1H), 6.63 (dd,1H), 5.10 (dd, 1H), 4.10 (q, 1H), 2.03 (m, 2H), 1.24 (m, 3H), 1.15 (t,3H), 1.02 (m, 1H), 0.84 (t, 3H).

Example 5.1B Ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoate (racemate)

150 mg (0.41 mmol) of ethyl 2-(4-iodo-2-oxopyridin-1(2H)-yl)hexanoate(racemate) and 97 mg (0.53 mmol) of 5-chloro-2-cyanophenylboronic acidin the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 114 mg (purity 95%, 70% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=373 (M+H)⁺

Example 5.1C2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoic acid(racemate)

113 mg (purity 95%, 0.29 mmol) of ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoate (racemate)were hydrolysed with lithium hydroxide according to General Method 6B.Yield: 64 mg (purity 78%, 50% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=345 (M+H)⁺

Example 6.1A Bromo(cyclopropylmethyl)magnesium

1.2 g (48.1 mmol) of magnesium turnings were initially charged in 30 mlof THF, a spatula tip of iodine was added and a solution of 6.5 g (48.1mmol, 1.0 eq.) of bromomethylcyclopropane in 15 ml of THF was slowlyadded dropwise. The reaction mixture was then stirred under reflux for 2h. After cooling to RT, the reaction solution was decanted from theremaining magnesium turnings and the crude solution was reacted further.

Example 6.1B Ethyl 3-cyclopropyl-2-hydroxypropanoate (racemate)

Under argon and with ice cooling, a solution of 5.4 g (purity 50%, 26.7mmol) of ethyl oxoacetate in 50 ml of THF was quickly added dropwise to7.6 g (48 mmol, 1.8 eq.) of bromo(cyclopropylmethyl)magnesium. Thereaction mixture was stirred for another 48 h, diluted with ethylacetate and quenched with water. Celite was added, and the reactionmixture was stirred for 5 min and then filtered. After phase separation,the organic phase was washed once with water, dried (sodium sulphate),filtered and concentrated under reduced pressure. Yield: 2.6 g (60% oftheory)

GC [Method 7]: R_(t)=2.49 min; MS (EI): m/z=158 (M)⁺

Example 6.1C Ethyl 3-cyclopropyl-2-[(methylsulphonyl)oxy]propanoate(racemate)

At RT, 2 ml (11.5 mmol, 2.4 eq.) ofN-ethyl-N-(propan-2-yl)propan-2-amine were added to a solution of 1.9 g(purity 40%, 4.8 mmol) of ethyl 3-cyclopropyl-2-hydroxypropanoate(racemate) in 100 ml of dichloromethane, followed by the quick addition,at 0° C., of 0.45 ml (5.8 mmol, 1.2 eq.) of methanesulphonyl chloride.The reaction mixture was stirred at RT for 2 h and then quenched withice. After phase separation, the organic phase was washed with threetimes with water and once with saturated sodium chloride solution. Thecombined organic phases were dried (sodium sulphate), filtered andconcentrated under reduced pressure. The crude product was used for thenext step without further purification.

Example 6.1D Ethyl2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate)

1.02 g (5.87 mmol) of 4-bromopyridin-2(1H)-one and 2.23 g (purity 56%,5.28 mmol) of ethyl 3-cyclopropyl-2-[(methylsulphonyl)oxy]propanoate(racemate) in the presence of 1.15 eq. of sodium hydride and 2.3 eq. oflithium bromide were reacted according to General Method 4C (stirred at65° C. overnight). Yield: 246 mg (13% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.67 (d, 1H), 6.76 (d, 1H), 6.54 (dd,1H), 5.76 (m, 1H), 5.12 (dd, 1H), 4.97 (m, 2H), 4.11 (q, 2H), 2.15 (q,2H), 1.92 (m, 2H), 1.15 (t, 3H).

Example 6.1E Ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoate(racemate)

250 mg (0.8 mmol) of ethyl2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) and214 mg (0.96 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid inthe presence of tetrakis(triphenylphosphine)palladium(0) were reactedaccording to General Method 2A. Yield: 35 mg (purity 87%, 9% of theory)of the title compound and 70 mg (22% of theory) of the product which isalready hydrolysed (Example 6.1F)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=414 (M+H)⁺

Example 6.1F2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoicacid (racemate)

35 mg (purity 87%, 0.07 mmol) of ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 60 mg (purity 88%, quant.)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=386 (M+H)⁺

Example 6.1G Methyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate(racemate)

105 mg (purity 94%, 0.26 mmol) of2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoicacid (racemate) and 1.1 eq. of methyl 4-aminobenzoate were reactedaccording to General Method 5A. After aqueous work-up, the crude productwas reacted further without further purification. Yield: 200 mg (purity48%, 72% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=519 (M+H)⁺

Example 6.2A 2-(4-Bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoicacid (racemate)

350 mg (1.1 mmol) of ethyl2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate)were hydrolysed with lithium hydroxide according to General Method 6B.Yield: 290 mg (purity 94%, 86% of theory)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIpos): m/z=286 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.14 (s, 1H), 7.65 (d, 1H), 6.74 (d,1H), 6.51 (dd, 1H), 5.75 (m, 1H), 5.11 (t, 1H), 4.98 (m, 2H), 2.15 (q,2H), 1.91 (m, 2H).

Example 6.2B tert-Butyl4-{[2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoyl]amino}benzoate(racemate)

290 mg (purity 94%, 0.95 mmol) of2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoic acid (racemate)and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according toGeneral Method 5A. Yield: 114 mg (purity 80%, 21% of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=461 (M+H)⁺

Example 6.2C tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate(racemate)

110 mg (purity 80%, 0.19 mmol) of tert-butyl4-{[2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoyl]amino}benzoate(racemate), 46 mg (0.19 mmol) of5-chloro-2-trifluoromethoxyphenylboronic acid and 22 mg (0.02 mmol) oftetrakis(triphenylphosphine)palladium(0) were taken up in 2.5 ml ofdioxane and 2.5 ml of saturated aqueous sodium carbonate solution andirradiated in a microwave at 130° C. for 12 min. The crude product waspurified by flash chromatography (silica gel 60, cyclohexane/ethylacetate mixtures). Yield: 77 mg (purity 92%, 64% of theory)

LC/MS [Method 1]: R_(t)=1.46 min; MS (ESIpos): m/z=577 (M+H)⁺

Example 7.1A Ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate(racemate)

544 mg (3.13 mmol) of 4-bromopyridin-2(1H)-one and 845 mg (3.3 mmol) ofethyl 2-bromo-3-phenylpropanoate (racemate) in the presence of 1.15 eq.of sodium hydride and 2.3 eq. of lithium bromide were reacted accordingto General Method 4C (stirred at 65° C. for 1.5 h). Yield: 572 mg (51%of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=350 (M+H)⁺

Example 7.1B Ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenylpropanoate(racemate)

572 mg (1.6 mmol) of ethyl2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-phenylpropanoate (racemate) and 330mg (1.8 mmol) of 5-chloro-2-cyanophenylboronic acid in the presence oftetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 300 mg (purity 94%, 43% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=407 (M+H)⁺

Example 7.1C2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenylpropanoicacid (racemate)

300 mg (purity 94%, 0.69 mmol) of ethyl2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenylpropanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 129 mg (purity 89%, 43% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=379 (M+H)⁺

Example 8.1A Ethyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate

5.0 g (28.7 mmol) of 4-bromopyridin-2(1H)-one and 5.3 g (31.6 mmol) ofethyl bromoacetate were reacted according to General Method 4B. Yield:6.2 g (83% of theory)

LC/MS [Method 3]: R_(t)=1.57 min; MS (ESIpos): m/z=260 (M+H)⁺

Example 8.1B Ethyl{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetate

2.04 g (7.8 mmol) of ethyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and1.98 g (8.6 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in thepresence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 2.89 g (quant.)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=360 (M+H)⁺

Example 8.1C Ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoate(racemate)

440 mg (1.22 mmol) of ethyl{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetateand 464 mg (1.84 mmol) of 2-(bromomethyl)pyridine monohydrobromide werereacted according to General Method 7A. Yield: 371 mg (purity 65%, 44%of theory) of the title compound and 270 mg (50% of theory) of theproduct which is already hydrolysed (Example 8.1D)

LC/MS [Method 2]: R_(t)=3.07 min; MS (ESIpos): m/z=451 (M+H)⁺

Example 8.1D2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoicacid (racemate)

350 mg (purity 65%, 0.51 mmol) of ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 240 mg (purity 80%, 90% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=423 (M+H)⁺

Example 8.1E tert-Butyl4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoyl]amino}benzoate(racemate)

Under argon and at 0° C., 707 mg (50% strength in ethyl acetate, 1.11mmol) of T3P and 0.29 ml (1.67 mmol) of N,N-diisopropylethylamine wereadded to a solution of 470 mg (purity 50%, 0.56 mmol) of2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoicacid (racemate) and 129 mg (0.67 mmol) of tert-butyl 4-aminobenzoate in45 ml of ethyl acetate. The reaction mixture was stirred at 60° C. for 1h, another 353 mg (50% strength in ethyl acetate, 0.56 mmol) of T3P and0.1 ml (0.56 mmol) of N,N-diisopropylethylamine were added and themixture was stirred at 60° C. for 1 h. After addition of water/ethylacetate and phase separation, the aqueous phase was extracted threetimes with ethyl acetate. The combined organic phases were dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography (silica gel 60,dichloromethane/methanol mixtures). Yield: 163 mg (purity 93%, 46% oftheory)

LC/MS [Method 1]: R_(t)=1.29 min; MS (ESIpos): m/z=598 (M+H)⁺

Example 9.1A Ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoate(racemate)

216 mg (0.6 mmol) of ethyl{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetateand 228 mg (0.9 mmol) of 3-(bromomethyl)pyridine monohydrobromide werereacted according to General Method 7A. Yield: 39 mg (14% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=451 (M+H)⁺

Example 9.1B2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoicacid (racemate)

39 mg (0.09 mmol) of ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 28 mg (purity 92%, 70% of theory)

LC/MS [Method 1]: R_(t)=0.74 min; MS (ESIpos): m/z=423 (M+H)⁺

Example 9.1C tert-Butyl4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoyl]amino}benzoate(racemate)

26 mg (purity 92%, 0.06 mmol) of2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. The reaction mixture was freed from DMFand the residue was stirred with ice-water. The crystals obtained werefiltered off, washed with water and dried under reduced pressure. Yield:33 mg (purity 94%, 92% of theory)

LC/MS [Method 1]: R_(t)=1.22 min; MS (ESIpos): m/z=598 (M+H)⁺

Example 9.2A tert-Butyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate

4.9 g (28.4 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl2-bromoacetate were reacted according to General Method 4B at 120° C.After aqueous work-up, the crude product was reacted further withoutfurther purification. Yield: 8.6 g (purity 91%, 95% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=288 (M+H)⁺

Example 9.2B tert-Butyl[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate

3.8 g (12 mmol) of tert-butyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and3.4 g (14.4 mmol) of 2-bromo-5-chlorophenylboronic acid in the presenceof tetrakis(triphenylphosphine)palladium(0) were reacted according toGeneral Method 2A. Yield: 3.9 g (purity 94%, 76% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=398 (M+H)⁺

Example 9.2C tert-Butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoate(racemate)

206 mg (purity 94%, 0.49 mmol) of tert-butyl[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 184 mg(0.73 mmol) of 3-(bromomethyl)pyridine monohydrobromide were reactedaccording to General Method 7A. Yield: 274 mg (purity 88%, quant.)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=489 (M+H)⁺

Example 9.2D2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoicacid (racemate

274 mg (purity 88%, 0.49 mmol) of tert-butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 244 mg (purity 57%, 65% of theory)

LC/MS [Method 1]: R_(t)=0.73 min; MS (ESIpos): m/z=433 (M+H)⁺

Example 9.2E Methyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoyl}amino)benzoate(racemate)

244 mg (purity 57%, 0.32 mmol) of2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoicacid (racemate) and 1.2 eq. of methyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 65 mg (purity 85%, 30% of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=566 (M+H)⁺

Example 10.1A Ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoate(racemate)

1.8 g (5.05 mmol) of ethyl{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}acetateand 1.9 g (7.6 mmol) of 4-(bromomethyl)pyridine monohydrobromide werereacted according to General Method 7A. Yield: 0.45 g (20% of theory)

LC/MS [Method 2]: R_(t)=2.42 min; MS (ESIpos): m/z=451 (M+H)⁺

Example 10.1B2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoicacid (racemate)

452 mg (1.0 mmol) of ethyl2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 289 mg (68% of theory)

LC/MS [Method 1]: R_(t)=0.70 min; MS (ESIpos): m/z=423 (M+H)⁺

Example 10.1C tert-Butyl4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoate(racemate)

626 mg (purity 50%, 0.74 mmol) of2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 155 mg (purity 94%, 33% oftheory)

LC/MS [Method 1]: R_(t)=1.17 min; MS (ESIpos): m/z=598 (M+H)⁺

Example 10.2A tert-Butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate(racemate)

1.3 g (purity 94%, 3.0 mmol) of tert-butyl[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 1.2 g (4.5mmol) of 4-(bromomethyl)pyridine monohydrobromide were reacted accordingto General Method 7A. Yield: 1.7 g (purity 89%, quant.)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=489 (M+H)⁺

Example 10.2B2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoicacid (racemate

1.7 g (purity 89%, 3.2 mmol) of tert-butyl2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoate(racemate) were hydrolysed with TFA according to General Method 6A.After work-up, the residue was triturated with diethyl ether and thesolid was filtered off and dried under reduced pressure. Yield: 1.8 g(purity 76%, 99% of theory)

LC/MS [Method 1]: R_(t)=0.64 min; MS (ESIpos): m/z=433 (M+H)⁺

Example 10.2C tert-Butyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)benzoate(racemate)

1.8 g (purity 76%, 3.2 mmol) of2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 734 mg (purity 92%, 35% oftheory)

LC/MS [Method 1]: Rt=1.16 min; MS (ESIpos): m/z=608 (M+H)⁺

Example 11.1A 4-Chloro-2-(5-fluoro-2-methoxypyridin-4-yl)benzonitrile

256 mg (1.5 mmol) of 5-fluoro-2-methoxypyridin-4-ylboronic acid and 295mg (1.34 mmol) of 2-bromo-4-chlorobenzonitrile were reacted according toGeneral Method 2A. The product was precipitated with water. Yield: 146mg (37% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=263 (M+H)⁺

Example 11.1B4-Chloro-2-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

210 mg (0.77 mmol) of4-chloro-2-(5-fluoro-2-methoxypyridin-4-yl)benzonitrile and pyridiniumhydrochloride were reacted according to General Method 3A. Yield: 126 mg(66% of theory)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIpos): m/z=249 (M+H)⁺

Example 11.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoate(racemate)

126 mg (0.51 mmol) of4-chloro-2-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.05eq. of tert-butyl 2-bromopropanoate (racemate) were reacted according toGeneral Method 4B at 100° C. Yield: 48 mg (25% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=377 (M+H)⁺

Example 11.1D2-[4-(5-Chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

46 mg (0.12 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 54 mg (purity 90%, quant.)

LC/MS [Method 1]: R_(t)=0.78 min; MS (ESIpos): m/z=321 (M+H)⁺

Example 11.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

54 mg (purity 90%, 0.15 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 51 mg (67% of theory)

LC/MS [Method 1]: Rt=1.23 min; MS (ESIpos): m/z=496 (M+H)⁺

Example 12.1A (5-Chloro-2-methoxypyridin-4-yl)boronic acid

10.0 g (69.65 mmol) of 5-chloro-2-methoxypyridine were reacted accordingto General Method 1A. The desired product precipitated on acidificationwith hydrochloric acid (2N). Yield: 10.44 g (purity 91%, 73% of theory)

LC/MS [Method 1]: R_(t)=0.50 min; MS (ESIpos): m/z=188 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.64 (br. s, 2H), 8.12 (s, 1H), 6.81(s, 1H), 3.82 (s, 3H).

Example 12.1B 4-Chloro-2-(5-chloro-2-methoxypyridin-4-yl)benzonitrile

5.36 g (purity 91%, 26.03 mmol) of 5-chloro-2-methoxypyridin-4-ylboronicacid and 5.12 g (23.66 mmol) of 2-bromo-4-chlorobenzonitrile in thepresence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. After work-up, the crude product was then purified by flashchromatography (silica gel 60, cyclohexane/dichloromethane mixtures).Yield: 4.11 g (purity 91%, 52% of theory)

LC/MS [Method 1]: R_(t)=1.17 min; MS (ESIpos): m/z=279 (M+H)⁺

Example 12.1C4-Chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

6.34 g (purity 93%, 21.12 mmol) of4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile and pyridiniumhydrochloride were reacted according to General Method 3A. Yield: 4.23 g(76% of theory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIpos): m/z=265 (M+H)⁺

Example 12.1D2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

910 mg (purity 57%, 1.96 mmol) of4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A, initially at RT for 2.5 h and then at 45° C.overnight. The desired product was obtained by precipitation withhydrochloric acid. Yield: 1.06 g (purity 78%, quant.)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=337 (M+H)⁺

Example 12.1E tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

135 mg (purity 93%, 0.37 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 281 mg (purity 58%, 85% oftheory)

LC/MS [Method 3]: R_(t)=2.69 min; MS (ESIpos): m/z=512 (M+H)⁺

Example 12.2A tert-Butyl5-[4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate)

150 mg (purity 82%, 0.37 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.2 eq. of tert-butyl5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate werereacted according to General Method 5A. Yield: 17.8 mg (purity 78%, 6%of theory)

LC/MS [Method 1]: R_(t)=1.17 min; MS (ESIpos): m/z=594 (M+H)⁺

Example 13.1A tert-Butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate

400 mg (purity 91%, 1.37 mmol) of4-chloro-2-(5-chloro-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2eq. of tert-butyl bromoacetate were reacted according to General Method4B at 100° C. Yield: 421 mg (80% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIneg): m/z=377 (M−H)⁻

Example 13.1B tert-Butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate(racemate)

349 mg (0.91 mmol) of tert-butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate and216 mg (1.18 mmol) of (iodomethyl)cyclopropane were reacted according toGeneral Method 7A. Yield: 245 mg (62% of theory)

LC/MS [Method 3]: R_(t)=2.75 min; MS (ESIpos): m/z=433 (M+H)⁺

Example 13.1C2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoicacid (racemate)

245 mg (0.57 mmol) of tert-butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate(racemate) were hydrolysed with 20 eq. of TFA according to GeneralMethod 6A. Yield: 268 mg (quant.)

LC/MS [Method 3]: R_(t)=2.21 min; MS (ESIpos): m/z=377 (M+H)⁺

Example 13.1D tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate(racemate)

268 mg (0.68 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 192 mg (51% of theory)

LC/MS [Method 1]: R_(t)=1.40 min; MS (ESIpos): m/z=552 (M+H)⁺

Example 14.1A 2-Bromo-4-chloro-1-(difluoromethyl)benzene

At 0° C., 0.9 ml (6.83 mmol) of diethylaminosulphur trifluoride wasadded to a solution of 1.0 g (4.56 mmol) of 2-bromo-4-chlorobenzaldehydein 12 ml of dichloromethane. The reaction mixture was stirred at RTovernight and then added dropwise to a saturated sodium bicarbonatesolution until no more evolution of carbon dioxide was noticeable. Afteraddition of ethyl acetate and phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and briefly (!) concentrated under reduced pressureand dried. Yield: 872 mg (79% of theory)

GC/MS [Method 7]: R_(t)=2.98 min; MS (EI): m/z=240 (M)⁺

Example 14.1B5-Chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-methoxypyridine

463 mg (purity 93%, 2.3 mmol) of (5-chloro-2-methoxypyridin-4-yl)boronicacid and 515 mg (2.1 mmol) of 2-bromo-4-chloro-1-(difluoromethyl)benzenein the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 305 mg (purity 77%, 34% of theory)

LC/MS [Method 1]: R_(t)=1.30 min; MS (ESIpos): m/z=304 (M+H)⁺

Example 14.1C5-Chloro-4-[5-chloro-2-(difluoromethyl)phenyl]pyridin-2(1H)-one

305 mg (purity 77%, 0.77 mmol) of5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-methoxypyridine and 20eq. of pyridinium chloride were reacted according to General Method 3A.After work-up, the crude product was purified by preparative HPLC(Reprosil C18, water/acetonitrile gradient). Yield: 179 mg (80% oftheory)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=290 (M+H)⁺

Example 14.1D2-{5-Chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid

118 mg (0.41 mmol) of5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]pyridin-2(1H)-one and 1.5eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A at 35° C. Yield: 112 mg (76% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=362 (M+H)⁺

Example 14.1E tert-Butyl4-[(2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

115 mg (0.32 mmol) of2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. After work-up, the crude product waspurified by preparative HPLC (Reprosil C18, water/acetonitrilegradient). Yield: 79 mg (46% of theory)

LC/MS [Method 1]: R_(t)=1.31 min; MS (ESIpos): m/z=537 (M+H)⁺

Example 15.1A5-Chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-methoxypyridine

443 mg (2.20 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 571mg (2.20 mmol) of 2-bromo-4-chloro-1-(trifluoromethyl)benzene in thepresence of XPhos precatalyst were reacted according to General Method2B. Yield: 193 mg (purity 93%, 25% of theory)

LC/MS [Method 1]: R_(t)=1.36 min; MS (ESIpos): m/z=322 (M+H)⁺

Example 15.1B5-Chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]pyridin-2(1H)-one

193 mg (purity 93%, 0.56 mmol) of5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-methoxypyridine andpyridinium hydrochloride were reacted according to General Method 3A.Yield: 123 mg (72% of theory)

LC/MS [Method 1]: R_(t)=0.97 min; MS (ESIpos): m/z=308 (M+H)⁺

Example 15.1C tert-Butyl2-{5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoate

123 mg (0.4 mmol) of5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]pyridin-2(1H)-one and1.05 eq. of tert-butyl 2-bromopropanoate (racemate) were reactedaccording to General Method 4B at 100° C. Yield: 81 mg (47% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=436 (M+H)⁺

Example 15.1D2-{5-Chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate)

81 mg (0.19 mmol) of2-{5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) were hydrolysed with TFA according to General Method 6A.Yield: 78 mg (purity 94%, quant.)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=380 (M+H)⁺

Example 15.1E2-{5-Chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid

78 mg (purity 94%, 0.19 mmol) of2-{5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 75 mg (70% of theory)

LC/MS [Method 1]: R_(t)=1.37 min; MS (ESIpos): m/z=555 (M+H)⁺

Example 16.1A (5-Cyano-2-methoxypyridin-4-yl)boronic acid

10.0 g (74.6 mmol) of 6-methoxypyridine-3-carbonitrile were reactedaccording to General Method 1A. Yield: 10.5 g (purity 89%, 70% oftheory)

LC/MS [Method 1]: R_(t)=0.51 min; MS (ESIpos): m/z=179 (M+H)⁺

Example 16.1B4-(5-Chloro-2-cyanophenyl)-6-methoxypyridine-3-carbonitrile

600 mg (purity 89%, 3.0 mmol) of 5-cyano-2-methoxypyridin-4-ylboronicacid and 649 mg (3.0 mmol) of 2-bromo-4-chlorobenzonitrile in thepresence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. After aqueous work-up, the crude product was triturated withwater and then with cyclohexane/ethyl acetate (7:3), and the solid wasfiltered off and dried under high vacuum. Yield: 399 mg (purity 94%, 46%of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=270 (M+H)⁺

Example 16.1C4-(5-Chloro-2-cyanophenyl)-6-oxo-1,6-dihydropyridine-3-carbonitrile

414 mg (purity 94%, 1.14 mmol) of4-(5-chloro-2-cyanophenyl)-6-methoxypyridin-3-carbonitrile andpyridinium hydrochloride were reacted according to General Method 3A.Yield: 312 mg (purity 91%, 77% of theory)

LC/MS [Method 1]: R_(t)=0.71 min; MS (ESIpos): m/z=256 (M+H)⁺

Example 16.1D2-[4-(5-Chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

312 mg (purity 91%, 1.11 mmol) of4-(5-chloro-2-cyanophenyl)-6-oxo-1,6-dihydropyridin-3-carbonitrile and1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A at 45° C. Yield: 240 mg (purity 85%, 56% of theory)

LC/MS [Method 1]: R_(t)=0.78 min; MS (ESIpos): m/z=328 (M+H)⁺

Example 16.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

240 mg (purity 85%, 0.62 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 93 mg (30% of theory)

LC/MS [Method 1]: R_(t)=1.17 min; MS (ESIneg): m/z=501 (M−H)⁻

Example 17.1A4-[5-Chloro-2-(difluoromethyl)phenyl]-6-methoxypyridine-3-carbonitrile

724 mg (3.0 mmol) of 5-chloro-2-methoxypyridin-4-ylboronic acid and 600mg (3.0 mmol) of 2-bromo-4-chloro-1-(difluoromethyl)benzene in thepresence of XPhos precatalyst were reacted according to General Method2B. Yield: 143 mg (purity 65%, 11% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=295 (M+H)⁺

Example 17.1B4-[5-Chloro-2-(difluoromethyl)phenyl]-6-oxo-1,6-dihydropyridine-3-carbonitrile

143 mg (purity 65%, 0.32 mmol) of4-[5-chloro-2-(difluoromethyl)phenyl]-6-methoxypyridin-3-carbonitrileand pyridinium hydrochloride were reacted according to General Method3A. Yield: 88 mg (99% of theory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIpos): m/z=281 (M+H)⁺

Example 17.1C2-{4-[5-Chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoicacid (racemate)

88 mg (0.31 mmol) of4-[5-chloro-2-(difluoromethyl)phenyl]-6-oxo-1,6-dihydropyridin-3-carbonitrileand 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted accordingto General Method 4A at 45° C. Yield: 88 mg (purity 92%, 73% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=353 (M+H)⁺

Example 17.1D tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

88 mg (purity 92%, 0.23 mmol) of2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 48 mg (36% of theory)

LC/MS [Method 1]: R_(t)=1.24 min; MS (ESIpos): m/z=528 (M+H)⁺

Example 18.1A 4-Iodo-6-methoxypyridine-3-carbonitrile

At −78° C., 19.4 ml of lithium diisopropylamide (2 molar inTHF/heptane/ethylbenzene, 1.3 eq.) were added to a solution of 4.0 g(29.8 mmol) of 6-methoxypyridine-3-carbonitrile in 120 ml of THF, andthe mixture was stirred at −78° C. for 1 h. At −78° C., a solution of9.1 g (35.8 mmol) of iodine in 20 ml of THF was then added, and thereaction mixture was stirred at −78° C. for 1 h and then carefully addedto saturated aqueous ammonium chloride solution. After addition of ethylacetate, the reaction mixture was extracted three times with ethylacetate. The combined organic phases were dried (magnesium sulphate),filtered and concentrated under reduced pressure. The crude product waspurified by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures). Yield: 4.0 g (purity 92%, 48% oftheory)

GC [Method 7]: R_(t)=5.08 min; MS (EI) m/z=260 (M)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.63 (s, 1H), 7.61 (s, 1H), 3.92 (s,1H).

Example 18.1B 4-Bromo-6-oxo-1,6-dihydropyridine-3-carbonitrile

4.5 g (purity 90%, 15.6 mmol) of 4-iodo-6-methoxypyridin-3-carbonitrileand 20 eq. of pyridinium hydrobromide were reacted according to GeneralMethod 3A. After aqueous work-up, the crude product was reacted furtherwithout further purification. Yield: 1.99 g (purity 77%, 49% of theory)of the title compound as a mixture with 11% of the analogous iodinecompound.

LC/MS [Method 1]: R_(t)=0.48 min; MS (ESIpos): m/z=199 (M+H)⁺

Example 18.1C 2-(4-Bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoic acid(racemate)

1.0 g (purity 77%, 3.87 mmol) of4-bromo-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of2-bromopropanoic acid (racemate) were reacted according to GeneralMethod 4A at 35-45° C. After aqueous work-up, the crude product wastriturated with cyclohexane/dichloromethane, and the solid was filteredoff and dried under high vacuum. Yield: 648 mg (purity 66%, 41% oftheory)

The filtrate was concentrated under reduced pressure and the residue waspurified by preparative HPLC (Reprosil C18, water/acetonitrilegradient). Yield: 110 mg (purity 91%, 10% of theory)

LC/MS [Method 1]: R_(t)=0.58 min; MS (ESIpos): m/z=271 (M+H)⁺

Example 18.1D tert-Butyl4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate)

750 mg (purity 70%, 1.94 mmol) of2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to GeneralMethod 5A. Yield: 704 mg (purity 70%, 57% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIneg): m/z=444 (M−H)⁻

Example 18.1E tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

127 mg (purity 70%, 0.2 mmol) of tert-butyl4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate) and 54 mg (0.24 mmol) of5-chloro-2-trifluoromethylphenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. After aqueous work-up, the crude product was triturated withwater and the solid was filtered off, dried and purified further byflash chromatography (silica gel 60, mobile phase: cyclohexane/ethylacetate mixtures). Yield: 124 mg (quant.)

LC/MS [Method 1]: R_(t)=1.28 min; MS (ESIpos): m/z=546 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.84 (d, 1H), 8.79 (s, 1H), 7.96(dd, 1H), 7.89 (d, 2H), 7.84 (m, 2H), 7.71 (d, 2H), 6.58 (s, 1H), 5.57(m, 1H), 1.76 (d, 3H), 1.54 (s, 9H).

Example 18.2A tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

127 mg (purity 70%, 0.2 mmol) of tert-butyl4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate) and 58 mg (0.24 mmol) of5-chloro-2-trifluoromethoxyphenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 107 mg (purity 94%, 89% of theory)

LC/MS [Method 1]: R_(t)=1.29 min; MS (ESIpos): m/z=562 (M+H)⁺

Example 18.3A tert-Butyl4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

127 mg (purity 70%, 0.2 mmol) of tert-butyl4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate) and 67 mg (0.24 mmol) of2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 66 mg (62% of theory)

LC/MS [Method 1]: R_(t)=1.28 min; MS (ESIpos): m/z=518 (M+H)⁺

Example 19.1A 4-Iodo-6-methoxypyridine-3-carbaldehyde

At −78° C., 25.1 ml (40.1 mmol, 1.1 eq.) of n-butyllithium were added toa solution of 5.7 ml (43.8 mmol, 1.2 eq.) ofN,N,N′-trimethylethylenediamine in 135 ml of THF, the mixture wasstirred for 45 min and 5.0 g (36.5 mmol) of6-methoxypyridine-3-carbaldehyde were added. After 45 min at −78° C., afurther 45.6 ml (72.9 mmol, 2.0 eq.) of n-butyllithium were added, thereaction mixture was stirred for 1 h, allowing the temperature to riseto −40° C., the mixture was stirred at −40° C. for a further 1 h andthen cooled back to −78° C., and a solution of 18.5 g (72.9 mmol) ofiodine in 90 ml of THF was added over a period of 50 min. Thetemperature was maintained at −78° C. for a further 4 h and then slowlyallowed to rise to RT overnight. The reaction mixture was poured into300 ml of saturated aqueous sodium chloride solution and, after phaseseparation, the aqueous phase was extracted twice with ethyl acetate.The combined organic phases were dried (sodium sulphate), filtered andconcentrated under reduced pressure. The residue was stirred withacetonitrile and filtered off, and the precipitate was dried under HV.Yield: 647 mg (purity 91%, 6% of theory)

Further precipitate from the mother liquor was filtered off and driedunder reduced pressure. Yield: 1050 mg (purity 70%, 8% of theory)

The combined mother liquors were concentrated under reduced pressure andthe residue was further purified by flash chromatography (silica gel 60,mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 1188 mg(purity 75%, 9% of theory)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=264 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.89 (s, 1H), 8.52 (s, 1H), 7.56 (s,1H), 3.94 (s, 3H).

Example 19.1B 5-(Difluoromethyl)-4-iodo-2-methoxypyridine

At 0° C., 0.7 ml (5.1 mmol, 1.5 eq.) of diethylaminosulphur trifluoridewere added to a solution of 1.0 g (purity 91%, 3.46 mmol) of4-iodo-6-methoxypyridin-3-carbaldehyde in 30 ml dichloromethane, and themixture was stirred at RT overnight. The reaction mixture was addeddropwise to a saturated sodium bicarbonate solution until no moreevolution of carbon dioxide was noticeable. After addition of ethylacetate and phase separation, the aqueous phase was extracted twice withethyl acetate. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried (sodium sulphate), filtered andbriefly (!) concentrated under reduced pressure and dried. Yield: 616 mg(purity 83%, 52% of theory)

LC/MS [Method 1]: R_(t)=1.04 min; MS (ESIpos): m/z=286 (M+H)⁺

Example 19.1C4-Chloro-2-[5-(difluoromethyl)-2-methoxypyridin-4-yl]benzonitrile

616 mg (purity 83%, 1.79 mmol) of5-(difluoromethyl)-4-iodo-2-methoxypyridine and 325 mg (1.79 mmol) of5-chloro-2-cyanophenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 223 mg (42% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIpos): m/z=295 (M+H)⁺

Example 19.1D4-Chloro-2-[5-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile

216 mg (0.73 mmol) of4-chloro-2-[5-(difluoromethyl)-2-methoxypyridin-4-yl]benzonitrile andpyridinium hydrobromide were reacted according to General Method 3A.Yield: 215 mg (purity 64%, 67% of theory)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIpos): m/z=281 (M+H)⁺

Example 19.1E2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

215 mg (purity 64%, 0.5 mmol) of4-chloro-2-[5-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrileand 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted accordingto General Method 4A at 50° C. Yield: 256 mg of crude product (purity64%, 95% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=353 (M+H)⁺

Example 19.1F tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

65 mg (purity 88%, 0.16 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 65 mg (76% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=528 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.85 (s, 1H), 8.30 (s, 1H), 8.02 (d,1H), 7.88 (d, 2H), 7.74 (m, 4H), 6.85 (br. t, 1H), 6.56 (s, 1H), 5.58(q, 1H), 1.74 (d, 3H), 1.55 (s, 9H).

Example 20.1A 2-Methoxy-5-trifluoromethylpyridin-4-ylboronic acid

10 g (56.5 mmol) of 2-methoxy-5-(trifluoromethyl)pyridine were reactedaccording to General Method 1A. Yield: 4.4 g (34% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.63 (br. s, 2H), 8.50 (s, 1H), 6.91(s, 1H), 3.92 (s, 3H).

Example 20.1B4-Chloro-2-[2-methoxy-5-(trifluoromethyl)pyridin-4-yl]benzonitrile

1.0 g (4.4 mmol) of 2-methoxy-5-trifluoromethylpyridin-4-ylboronic acidand 0.95 g (4.4 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 351 mg (purity 71%, 18% of theory)

LC/MS [Method 1]: R_(t)=1.19 min; MS (ESIpos): m/z=313 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.76 (s, 1H), 8.07 (d, 1H), 7.81 (dd,1H), 7.77 (s, 1H), 7.16 (s, 1H), 4.01 (s, 3H).

Example 20.1C4-Chloro-2-[2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-4-yl]benzonitrile

450 mg (purity 71%, 1.02 mmol) of4-chloro-2-[2-methoxy-5-(trifluoromethyl)pyridin-4-yl]benzonitrile and20 eq. of pyridinium hydrochloride were reacted according to GeneralMethod 3A. After aqueous work-up, the crude product was purified byflash chromatography (silica gel 60, dichloromethane/methanol mixtures).Yield: 456 mg (purity 86%, quant.)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=299 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.58 (br. s, 1H), 8.09 (s, 1H), 8.03(d, 1H), 7.77 (dd, 1H), 7.74 (s, 1H), 6.51 (s, 1H).

Example 20.1D2-[4-(5-Chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoicacid (racemate)

456 mg (purity 86%, 1.31 mmol) of4-chloro-2-[2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-4-yl]benzonitrileand 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted accordingto General Method 4A at 50° C. Yield: 515 mg (purity 51%, 54% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=371 (M+H)⁺

Example 20.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

515 mg (purity 51%, 0.71 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 251 mg (purity 79%, 51% oftheory)

LC/MS [Method 1]: R_(t)=1.30 min; MS (ESIpos): m/z=546 (M+H)⁺

Example 21.1A 2,5-Dimethoxypyridin-4-ylboronic acid

11.53 g (82.9 mmol) of 2,5-dimethoxypyridine were reacted according toGeneral Method 1A. The desired product precipitated out afteracidification of the aqueous phase. Yield: 9.53 g (61% of theory)

LC/MS [Method 1]: R_(t)=0.47 min; MS (ESIpos): m/z=184 (M+H)⁺

Example 21.1B 4-Chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile

7.87 g (purity 95%, 40.86 mmol) of 2,5-dimethoxypyridin-4-ylboronic acidand 8.85 g (40.86 mmol) of 2-bromo-4-chlorobenzonitrile in the presenceof [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 6.23 g (purity 92%, 51% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=275 (M+H)⁺

Example 21.1C4-Chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

7.23 g (purity 92%, 24.21 mmol) of4-chloro-2-(2,5-dimethoxypyridin-4-yl)benzonitrile and pyridiniumhydrochloride were reacted according to General Method 3A. Yield: 6.66 g(purity 91%, 96% of theory)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIpos): m/z=261 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.45 (br. s, 1H), 7.98 (d, 1H),7.75-7.67 (m, 2H), 7.29 (br. s, 1H), 6.43 (s, 1H), 3.64 (s, 3H).

Example 21.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

599 mg (purity 87%, 2.00 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A at 90° C. Yield: 716 mg (purity 68%, 73% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=333 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.73 (m, 2H), 7.48 (s,1H), 6.50 (s, 1H), 5.17 (q, 1H), 3.65 (s, 3H), 1.61 (d, 3H).

Example 21.1E tert-Butyl4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

1.53 g (purity 73%, 3.35 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 1.52 g (purity 93%, 83% oftheory)

LC/MS [Method 1]: R_(t)=1.19 min; MS (ESIpos): m/z=508 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.72 (s, 1H), 8.01 (d, 1H), 7.87 (d,2H), 7.74 (m, 4H), 7.46 (s, 1H), 6.53 (s, 1H), 5.59 (q, 1H), 3.70 (s,3H), 1.74 (d, 3H), 1.54 (s, 9H).

Example 21.2A 4-(5-Chloro-2-nitrophenyl)-2,5-dimethoxypyridine

215 mg (purity 85%, 1.0 mmol) of 2,5-dimethoxypyridin-4-ylboronic acidand 236 mg (1.0 mmol) of 2-bromo-4-chloro-1-nitrobenzene in the presenceof XPhos precatalyst were reacted according to General Method 2B. Yield:124 mg (purity 93%, 39% of theory)

LC/MS [Method 2]: R_(t)=3.22 min; MS (ESIpos): m/z=295 (M+H)⁺

Example 21.2B 4-(5-Chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one

124 mg (purity 93%, 0.39 mmol) of4-(5-chloro-2-nitrophenyl)-2,5-dimethoxypyridine and pyridiniumhydrochloride were reacted according to General Method 3A. Yield: 115 mg(purity 85%, 89% of theory)

LC/MS [Method 1]: R_(t)=0.74 min; MS (ESIpos): m/z=281 (M+H)⁺

Example 21.2C2-[4-(5-Chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

115 mg (purity 85%, 0.35 mmol) of4-(5-chloro-2-nitrophenyl)-5-methoxypyridin-2(1H)-one and 1.5 eq. of2-bromopropanoic acid (racemate) were reacted according to GeneralMethod 4A at 50° C. Yield: 43 mg (35% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=353 (M+H)⁺

Example 21.2D tert-Butyl4-({2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

Under argon and at RT, 25 mg (0.13 mmol) of tert-butyl 4-aminobenzoate,44 μl (0.26 mmol) of N,N-diisopropylethylamine and 74 μl (50% strengthin DMF, 0.13 mmol) of T3P were added to a solution of 30 mg (0.09 mmol)of2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) in 2 ml of DMF, and the mixture was stirred at RT for 2h. The reaction mixture was concentrated under reduced pressure and theresidue was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 32 mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.19 min; MS (ESIpos): m/z=528 (M+H)⁺

Example 22.1A tert-Butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

516 mg (purity 91%, 1.8 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.2eq. of tert-butyl bromoacetate were reacted according to General Method4B at 100° C. Yield: 464 mg (68% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=375 (M+H)⁺

Example 22.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate(racemate)

464 mg (1.24 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and293 mg (1.61 mmol) of (iodomethyl)cyclopropane were reacted according toGeneral Method 7A. Yield: 379 mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.18 min; MS (ESIpos): m/z=429 (M+H)⁺

Example 22.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate(racemate)

378 mg (0.88 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoate(racemate) were hydrolysed with 20 eq. of TFA according to GeneralMethod 6A. Yield: 420 mg (purity 92%, quant.)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=373 (M+H)⁺

Example 22.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate(racemate)

420 mg (purity 92%, 1.04 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoicacid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 348 mg (61% of theory)

LC/MS [Method 1]: R_(t)=1.29 min; MS (ESIpos): m/z=548 (M+H)⁺

Example 23.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoate(racemate)

309 mg (0.8 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and155 mg (1.04 mmol) of 3-bromoprop-1-yne were reacted according toGeneral Method 7A. Yield: 288 mg (87% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=413 (M+H)⁺

Example 23.1B2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoicacid (racemate)

288 mg (0.7 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 295 mg (purity 85%, quant.)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIpos): m/z=357 (M+H)⁺

Example 23.1C tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoyl}amino)benzoate(racemate)

295 mg (purity 85%, 0.70 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 91 mg (24% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=532 (M+H)⁺

Example 24.1A 6-Methoxypyridin-3-ol

At RT, 50 g (327 mmol) of 6-methoxypyridin-3-ylboronic acid were addedto a solution of 46.0 g (392 mmol) of N-methylmorpholine N-oxide in 500ml of dichloromethane, and the mixture was stirred at 50° C. for 14 h.Additional N-methylmorpholine N-oxide was added until the reaction hadgone to completion. The reaction mixture was concentrated under reducedpressure and the crude product was purified by flash chromatography(silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 32.9 g (80%of theory)

LC/MS [Method 1]: R_(t)=0.37 min; MS (ESIpos): m/z=126 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=9.27 (s, 1H), 7.67 (d, 1H), 7.16 (dd,1H), 6.66 (d, 1H), 3.74 (s, 3H).

Example 24.1B 2-Methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine

10.1 g (119.9 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran and 1.4 g (8.0mmol, 0.1 eq.) of 4-toluenesulphonic acid were added to a solution of10.0 g (79.9 mmol) of 6-methoxypyridin-3-ol in 150 ml ofdichloromethane, and the mixture was stirred at RT for 5 d. Afteraddition of water/dichloromethane and phase separation, the aqueousphase was extracted with dichloromethane. The combined organic phaseswere dried (sodium sulphate), filtered and concentrated under reducedpressure. Yield: 17.3 g (100% of theory)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIpos): m/z=210 (M+H)⁺

Example 24.1C 4-Iodo-2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine

At −78° C., 13.6 ml (90.1 mmol, 1.2 eq.) of 1,2-bis(dimethylamino)ethaneand 54.0 ml (86.4 mmol, 1.15 eq.) of n-butyllithium were added to asolution of 16.2 g (75.1 mmol) of2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 250 ml of THF, andthe mixture was stirred at −78° C. for 1 h. 24.8 g (97.6 mmol, 1.3 eq.)of iodine were then added, and the reaction mixture was stirred at −78°C. for 1 h and then allowed to warm to RT overnight. The reactionmixture was quenched with water and extracted three times with ethylacetate. The combined organic phases were washed with saturated aqueoussodium thiosulphate solution, dried (sodium sulphate), filtered andconcentrated under reduced pressure. Yield: 25.1 g (purity 82%, 82% oftheory)

LC/MS [Method 1]: R_(t)=1.18 min; MS (ESIpos): m/z=336 (M+H)⁺

Example 24.1D 4-Iodo-6-methoxypyridin-3-ol

50 ml (3 molar, 150 mmol) of hydrochloric acid were added to a solutionof 25.1 g (purity 82%, 61.3 mmol) of4-iodo-2-methoxy-5-(tetrahydro-2H-pyran-2-yloxy)pyridine in 50 ml ofdioxane and 50 ml of water, and the mixture was stirred at RT for 2 h.The reaction mixture was then filtered and the precipitate was rinsedwith water and dried under high vacuum. Yield: 13.5 g (purity 93%, 81%of theory)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIpos): m/z=252 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.70 (s, 1H), 7.22 (s, 1H), 3.74 (s,3H).

Example 24.1E 4-Iodo-5-isopropoxy-2-methoxypyridine

At 0° C., 758 mg (4.5 mmol) of 2-iodopropane and 948 mg (6.9 mmol, 2eq.) of potassium carbonate were added to a solution of 861 mg (3.4mmol) of 4-iodo-6-methoxypyridin-3-ol in 15 ml of acetone and themixture was stirred at 80° C. overnight and concentrated under reducedpressure. After addition of water/ethyl acetate and phase separation,the aqueous phase was extracted with ethyl acetate. The combined organicphases were dried (sodium sulphate), filtered and concentrated underreduced pressure. Yield: 741 mg (73% of theory)

LC/MS [Method 1]: R_(t)=1.16 min; MS (ESIpos): m/z=294 (M+H)⁺

Example 24.1F 4-Iodo-5-isopropoxypyridin-2(1H)-one

741 mg (2.53 mmol) of 4-iodo-2-methoxy-5-(propan-2-yloxy)pyridine and 20eq. of pyridinium hydrobromide were reacted according to General Method3A. Yield: 413 mg (purity 92%) of a mixture (1.4:1) of the iodinecompound 24.1F and the analogous bromine compound

LC/MS [Method 1]: bromine compound: R_(t)=0.71 min; MS (ESIpos): m/z=232(M+H)⁺; iodine compound: R_(t)=0.74 min; MS (ESIpos): m/z=280 (M+H)⁺

Example 24.1G 2-(4-Iodo-5-isopropoxy-2-oxopyridin-1(2H)-yl)propanoicacid (racemate)

414 mg (purity 92%) of a mixture (1.4:1) of4-iodo-5-(propan-2-yloxy)pyridin-2(1H)-one and the analogous brominecompound were reacted with 1.5 eq. of 2-bromopropanoic acid (racemate)according to General Method 4A at 50° C. Yield: 771 mg (purity 90%) of amixture (1.6:1) of the iodine compound 24.1G and the analogous brominecompound

LC/MS [Method 1]: bromine compound: R_(t)=0.78 min; MS (ESIpos): m/z=304(M+H)⁺; iodine compound: R_(t)=0.80 min; MS (ESIpos): m/z=352 (M+H)⁺

Example 24.1H tert-Butyl4-{[2-(4-iodo-5-isopropoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate)

771 mg (purity 90%) of a mixture (1.6:1) of2-[4-iodo-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoic acid(racemate) and the analogous bromine compound were reacted with 1.2 eq.of tert-butyl 4-aminobenzoate according to General Method 5A. Yield: 100mg of a mixture (3:1) of the iodine compound 24.1H and the analogousbromine compound

LC/MS [Method 1]: bromine compound: R_(t)=1.22 min; MS (ESIpos): m/z=479(M+H)⁺; iodine compound: R_(t)=1.24 min; MS (ESIpos): m/z=527 (M+H)⁺

Example 24.1I tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-isopropoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

100 mg of a mixture (3:1) of tert-butyl4-({2-[4-iodo-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) and the analogous bromine compound and 41 mg (0.23 mmol) of5-chloro-2-cyanophenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. Yield: 31 mg (29% of theory)

LC/MS [Method 1]: R_(t)=1.31 min; MS (ESIpos): m/z=536 (M+H)⁺

Example 25.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoate(racemate)

309 mg (0.80 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and191 mg (1.04 mmol) of isobutyl iodide were reacted according to GeneralMethod 7A. Yield: 178 mg (purity 92%, 48% of theory) of product.

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=431 (M+H)⁺

Example 25.1B2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoicacid (racemate)

178 mg (purity 92%, 0.38 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoicacid (racemate) were hydrolysed with TFA according to General Method 6A.Yield: 165 mg (purity 85%, 98% of theory)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIpos): m/z=375 (M+H)⁺

Example 25.1C tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate(racemate)

166 mg (purity 85%, 0.38 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 127 mg (60% of theory)

LC/MS [Method 1]: R_(t)=1.33 min; MS (ESIpos): m/z=550 (M+H)⁺

Example 26.1A2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate)

159 mg (purity 82%, 0.5 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5eq. of 2-bromobutanoic acid (racemate) were reacted according to GeneralMethod 4A at 50° C. Yield: 55 mg (32% of theory)

LC/MS [Method 1]: R_(t)=0.85 min; MS (ESIpos): m/z=347 (M+H)⁺

Alternative Synthesis:

Under argon and at RT, 7.8 ml (101.8 mmol, 10 eq.) of trifluoroaceticacid were added to a solution of 4.1 g (10.2 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate(racemate) in 40 ml of dichloromethane, the mixture was stirred at RTfor 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acidwere added, the mixture was stirred at RT for 1 h, a further 7.8 ml(101.8 mmol, 10 eq.) of trifluoroacetic acid were added and the mixturewas stirred at RT for 1 h. Once the reaction had gone to completion, thereaction mixture was concentrated under reduced pressure and the residuewas co-evaporated in each case three times with dichloromethane and oncewith toluene and dried under reduced pressure. The residue was taken upin 100 ml of ethyl acetate and washed repeatedly with a strongly dilutedaqueous sodium bicarbonate solution (where the pH of the washing watershould not exceed pH 3-4 since otherwise the product is well soluble inwater). The organic phase was subsequently dried (sodium sulphate),filtered and concentrated under reduced pressure. The residue wastriturated with methyl tert-butyl ether, filtered, washed twice withmethyl tert-butyl ether and dried under reduced pressure. Yield: 2.9 g(83% of theory)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIpos): m/z=347 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.97 (s, 1H), 7.99 (d, 1H),7.77-7.70 (m, 2H), 7.41 (s, 1H), 6.49 (s, 1H), 5.09 (dd, 1H), 3.64 (s,3H), 2.21-2.09 (m, 2H), 0.84 (t, 3H).

Example 26.1B tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate(racemate)

55 mg (0.16 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 68 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=522 (M+H)⁺

Example 26.2A tert-Butyl5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 84 mg (purity 90%, 0.28 mmol, 1.1 eq.) of tert-butyl5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate werereacted according to General Method 5A. The crude product was purifiedby preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield:17 mg (purity 70%, 8% of theory)

LC/MS [Method 1]: R_(t)=1.13 min; MS (ESIpos): m/z=604 (M+H)⁺.

Example 26.3A tert-Butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 74 mg (0.27 mmol, 1.1 eq.) of tert-butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate werereacted according to General Method 5A. The crude product was purifiedby preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield:112 mg (77% of theory)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=592 (M+H)⁺.

Example 26.4A Ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-benzimidazole-2-carboxylate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl6-amino-1H-benzimidazole-2-carboxylate were reacted according to GeneralMethod 5A. The crude product was purified by preparative HPLC (ReprosilC18, acetonitrile/water+0.1% formic acid gradient). Yield: 86 mg (64% oftheory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=534 (M+H)⁺.

Example 26.5A Ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl6-amino-1H-indole-2-carboxylate were reacted according to General Method5A. The crude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 75 mg (55% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=533 (M+H)⁺.

Example 26.6A Ethyl5-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl5-amino-1H-indole-2-carboxylate were reacted according to General Method5A. The crude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 94 mg (70% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=533 (M+H)⁺.

Example 27.1A 1,3-Dithiane-2-carboxylic acid

9.20 g (100 mmol) of glyoxalic acid monohydrate, 11.1 ml (110 mmol) of1,3-propanedithiol and 1.72 g (10.0 mmol) of para-toluenesulphonic acidwere heated in 200 ml of toluene under reflux for 3 h. The reactionmixture was cooled to RT and extracted three times with 100 ml ofsaturated aqueous sodium bicarbonate solution. The combined aqueousphases were washed with 200 ml of diethyl ether, acidified with aqueoushydrochloric acid (6N) and extracted four times with 200 ml of ethylacetate. The combined organic phases were dried over magnesium sulphateand filtered, and the solvent was removed under reduced pressure. Theresidue was used for the next step without further purification. Yield:8.0 g (47% of theory)

LC/MS [Method 4]: R_(t)=0.78 min; MS (ESIneg): m/z=163 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.0 (br. s, 1H), 4.59 (s, 1H),3.17-3.08 (m, 2H), 2.76-2.68 (m, 2H), 1.98-1.79 (m, 2H).

Example 27.1B tert-Butyl 1,3-dithiane-2-carboxylate

A little at a time, 10.5 g (48.2 mmol) of di-tert-butyl dicarbonate and1.68 g (13.8 mmol) of dimethylaminopyridine were added to a solution of7.54 mmol (45.9 mmol) of 1,3-dithiane-2-carboxylic acid in 28 ml ofTHF/tert-butanol (1:1). The resulting reaction mixture was stirred at RTovernight and diluted with 150 ml of ethyl acetate. The organic phasewas washed successively with 100 ml of saturated aqueous ammoniumchloride solution, 100 ml of water and 100 ml of saturated aqueoussodium chloride solution, dried over sodium sulphate and filtered, andthe solvent was removed under reduced pressure. The residue was purifiedby flash chromatography and the title compound was obtained as acrystalline solid. Yield: 6.79 g (66% of theory)

LC/MS [Method 4]: R_(t)=2.28 min; MS (ESIpos): m/z=221 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.50 (s, 1H), 3.20-3.12 (m, 2H),2.73-2.65 (m, 2H), 1.92-1.80 (m, 2H), 1.45 (s, 9H).

Example 27.1C 1-Iodo-2-methoxyethane

10.4 g (75.0 mmol) of 1-bromo-2-methoxyethane and 13.5 g (90.0 mmol) ofsodium iodide were stirred in 75 ml of acetone at RT for 14 h. Thesolvent was then removed at 25° C. and 220 mbar and the residue wastaken up in 100 ml of ethyl acetate. The organic phase was twice washedwith 50 ml of water, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude product was usedfor the next step without further purification. Yield: 12.5 g (90% oftheory)

GC/MS [Method 9]: Rt=1.56 min; MS: m/z=186 (M)⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.66 (t, 2H), 3.41 (s, 3H), 3.26 (t,2H).

Example 27.1D tert-Butyl 2-(2-methoxyethyl)-1,3-dithiane-2-carboxylate

10.2 g (46.1 mmol) of tert-butyl 1,3-dithiane-2-carboxylate and 12.0 g(64.5 mmol) of 1-iodo-2-methoxyethane were initially charged in 127 mlof dimethylformamide, the mixture was cooled to 0° C. and 6.21 g (55.3mmol) of potassium tert-butoxide were added. The resulting reactionmixture was stirred at 0° C. for 1 h and at RT for 16 h. The reactionmixture was added to 1.5 l of a 1:2 mixture of ice and saturated aqueousammonium chloride solution and extracted three times with 300 ml ofdiethyl ether. The combined organic phases were dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The crude product was used for the next step without furtherpurification. Yield: 11.1 g (87% of theory)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=177(M-COO-tert-Butyl)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.46 (t, 2H), 3.19 (s, 3H), 3.13-3.06(m, 2H), 2.78-2.72 (m, 2H), 2.15 (t, 2H), 2.08-1.98 (m, 1H), 1.75-1.64(m, 1H), 1.45 (s, 9H).

Example 27.1E tert-Butyl 4-methoxy-2-oxobutanoate

A solution of 10.6 g (38.1 mmol) of tert-butyl2-(2-methoxyethyl)-1,3-dithiane-2-carboxylate in 365 ml of acetone and18 ml of water was added dropwise to a solution, cooled to −18° C., of54.2 g (305 mmol) of N-bromosuccinimide in 365 ml of acetone and 18 mlof water such that the internal temperature did not exceed −5° C. Afterthe addition had ended, the mixture was stirred for another 10 min andthe reaction was then terminated using 630 ml of sodium sulphitesolution (1N). 420 ml of n-heptane were added to the reaction mixtureand, after phase separation, the aqueous phase was extracted three timeswith 315 ml of ethyl acetate. The combined organic phases were driedover sodium sulphate and filtered, and the solvent was removed at 25° C.and 75 mbar. The resulting suspension was stirred with 100 ml ofn-hexane and the precipitate was filtered off. The solvent was removedunder reduced pressure, giving the target compound. Yield: 5.28 g (59%of theory)

GC/MS [Method 9]: Rt=3.20 min; MS: m/z=188 (M)⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.70 (t, 2H), 3.34 (s, 3H), 3.04 (t,2H), 1.55 (s, 9H).

Example 27.1F tert-Butyl 2-hydroxy-4-methoxybutanoate (racemate)

At 0° C., 1.05 g (27.6 mmol) of sodium borohydride were added a littleat a time to a solution of 5.20 g (27.6 mmol) of tert-butyl4-methoxy-2-oxobutanoate in 68.5 ml of methanol. The reaction mixturewas stirred for another 5 min, 5 ml of water were added and the pH wasadjusted to 6 using aqueous hydrochloric acid (1N). Methanol was removedunder reduced pressure at 30° C. and the aqueous phase that remained wasextracted three times with 50 ml of diethyl ether. The combined organicphases were dried over magnesium sulphate and filtered, and the solventwas removed under reduced pressure (25° C., 70 mbar). Yield: 4.48 g (77%of theory)

GC/MS [Method 9]: Rt=3.07 min; MS: m/z=190 (M)⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.19-4.15 (m, 1H), 3.55 (t, 2H), 3.33(s, 3H), 3.08 (d, 1H), 2.10-2.02 (m, 1H), 1.91-1.83 (m, 1H), 1.49 (s,9H).

Example 27.1G tert-Butyl4-methoxy-2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate)

3.15 g (16.6 mmol) of tert-butyl 2-hydroxy-4-methoxybutanoate (racemate)in 158 ml of dichloromethane and 2.89 ml (24.8 mmol) of lutidine and4.20 ml (24.8 mmol) of trifluoromethanesulphonic anhydride were reactedaccording to General Method 8A. Yield: 4.44 g (83% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=5.18 (dd, 1H), 3.56-3.44 (m, 2H), 3.34(s, 3H), 2.31-2.23 (m, 1H), 2.21-2.12 (m, 1H), 1.51 (s, 9H).

Example 27.1H tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate(racemate)

A little at a time, 405 mg (10.1 mmol) of sodium hydride (60% in mineraloil) were added to a suspension of 2.4 g (9.2 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in 70ml of tetrahydrofuran, and the mixture was stirred at RT for another 1h. 4.45 g (13.8 mmol) of tert-butyl4-methoxy-2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) as asolution in 20 ml of THF were quickly added dropwise to the resultingreaction solution, and after the addition had ended the mixture wasstirred at RT for another 1.5 h. The reaction was terminated by additionof 150 ml of saturated aqueous ammonium chloride solution and 150 ml ofmethyl tert-butyl ether. The phases were separated and the aqueous phasewas extracted three times with 130 ml of methyl tert-butyl ether. Thecombined organic phases were dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The crude productwas purified by flash chromatography (120 g silica cartridge, 85 ml/min,cyclohexane/ethyl acetate gradient), giving the title compound. Yield:1.73 g (43% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=433 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.74 (s, 1H), 7.73 (dd,1H), 7.38 (s, 1H), 6.49 (s, 1H), 5.11 (t, 1H), 3.64 (s, 3H), 3.41-3.35(m, 1H), 3.23-3.13 (m, 1H), 3.20 (s, 3H), 2.36-2.31 (m, 2H), 1.40 (s,9H).

Example 27.1I2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate)

1.99 g (4.60 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) in 46 ml of dichloromethane and 13.3 ml (172 mmol) ofTFA were reacted according to General Method 6A. Yield: 1.58 g (91% oftheory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIneg): m/z=374 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.0 (br. s, 1H), 7.99 (d, 1H),7.75-7.72 (m, 2H), 7.42 (s, 1H), 6.48 (s, 1H), 5.13 (t, 1H), 3.63 (s,3H), 3.41-3.31 (m, 1H), 3.19 (s, 3H), 3.15-3.10 (m, 1H), 2.38-2.33 (m,2H).

Example 27.1J Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate(racemate)

1.50 g (3.98 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate), 658 mg (3.98 mmol) of ethyl 4-aminobenzoate, 566 mg(3.98 mmol) of Oxima and 620 μl (3.98 mmol) of DIC in 39 ml ofdimethylformamide were reacted according to General Method 5B.Filtration gave the title compound. Yield: 1.87 g (85% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=524 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.94 (d,2H), 7.79 (d, 2H), 7.65 (s, 1H), 7.74 (dd, 1H), 7.51 (s, 1H), 6.53 (s,1H), 5.76 (t, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 3.43-3.25 (m, 2H), 3.21(s, 3H), 2.45-2.40 (m, 2H), 1.31 (t, 3H).

Example 28.1A (2S)-2-Methoxypropyltrifluoromethanesulphonate

645 mg (7.16 mmol) of (S)-(+)-2-methoxypropanol and 1.27 ml (7.52 mmol,1.05 eq.) of trifluoromethanesulphonic anhydride in the presence of 917μl (7.87 mmol, 1.1 eq.) of 2,6-dimethylpyridine were reacted accordingto General Method 8A. The crude product was reacted in the next stepwithout further purification.

Example 28.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-L-glycero-pentonate(mixture of enantiomerically pure diastereomers 1 and 2)

450 mg (1.15 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.27 ml (1.27 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 384 mg (1.73 mmol, 1.5eq.) of (2S)-2-methoxypropyl trifluoromethanesulphonate were reactedaccording to General Method 7B. Yield: 375 mg (73% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=447 (M+H)⁺.

Example 28.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-L-glycero-pentonicacid (mixture of enantiomerically pure diastereomers 1 and 2)

375 mg (0.84 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-L-glycero-pentonate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 391 mg (purity 92%,quant.)

LC/MS [Method 2]: diastereomer 1: R_(t)=2.28 min; MS (ESIpos): m/z=391(M+H)⁺; diastereomer 2: R_(t)=2.36 min; MS (ESIpos): m/z=391 (M+H)⁺.

Example 28.1D tert-Butyl4-({(4S)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

391 mg (purity 92%, 0.92 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-L-glycero-pentonicacid (mixture of enantiomerically pure diastereomers 1 and 2) and 196 mg(1.01 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 387 mg (71% of theory)

LC/MS [Method 1]: diastereomer 1: R_(t)=1.23 min; MS (ESIpos): m/z=566(M+H)⁺; diastereomer 2: R_(t)=1.24 min; MS (ESIpos): m/z=566 (M+H)⁺.

Example 29.1A (2R)-2-Methoxypropan-1-ol

Under argon and at 0° C., 858 μl (8.39 mmol, 1.8 eq.) of borane/dimethylsulphide complex were added dropwise to a solution of 500 mg (4.66 mmol)of (R)-(+)-2-methoxypropionic acid in 10 ml of dichloromethane, thereaction mixture was stirred at RT overnight and aqueous sodiumhydroxide solution (2M) was then added dropwise. After phase separation,the aqueous phase was extracted with dichloromethane. The combinedorganic phases were dried (sodium sulphate), filtered, concentratedunder reduced pressure (water bath <20° C., pressure >300 mbar) anddried. Yield: 490 mg (quant.)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.55 (t, 1H), 3.40-3.31 (m, 1H),3.30-3.20 (m, 2H), 3.24 (s, 3H), 1.02 (d, 3H).

Example 29.1B (2R)-2-Methoxypropyl trifluoromethanesulphonate

490 mg of (2R)-2-methoxypropan-1-ol and 1.01 ml (5.98 mmol, 1.1 eq.) oftrifluoromethanesulphonic anhydride in the presence of 834 μl (5.98mmol, 1.1 eq.) of triethylamine were reacted according to General Method8A. The crude product was reacted in the next step without furtherpurification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.39 (dd, 1H), 4.17 (dd, 1H),3.66-3.58 (m, 1H), 3.33 (s, 3H), 1.09 (d, 3H).

Example 29.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-D-glycero-pentonate(mixture of enantiomerically pure diastereomers 1 and 2)

500 mg (1.24 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.36 ml (1.36 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 861 mg (purity 80%, 3.1mmol, 2.5 eq.) of (2R)-2-methoxypropyl trifluoromethanesulphonate werereacted according to General Method 7B. Yield: 99 mg (19% of theory)

Example 29.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-D-glycero-pentonicacid (mixture of enantiomerically pure diastereomers 1 and 2)

99 mg (0.22 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-D-glycero-pentonate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 88 mg (purity 88%, 91%of theory)

LC/MS [Method 8]: diastereomer 1: R_(t)=1.05 min; MS (ESIpos): m/z=391(M+H)⁺; diastereomer 2: R_(t)=1.07 min; MS (ESIpos): m/z=391 (M+H)⁺.

Example 29.1E tert-Butyl4-({(4R)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

88 mg (purity 88%, 0.20 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,3,5-trideoxy-4-O-methyl-D-glycero-pentonicacid (mixture of enantiomerically pure diastereomers 1 and 2) and 42 mg(0.22 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 51 mg (46% of theory) mixture ofenantiomerically pure diastereomers 1 and 2 and 26 mg (23% of theory) ofdiastereomer 1.

LC/MS [Method 8]: diastereomer 1: R_(t)=1.51 min; MS (ESIneg): m/z=564(M−H)⁻; diastereomer 2: R_(t)=1.52 min; MS (ESIneg): m/z=564 (M−H)⁻.

Example 30.1A (2R)-Tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate

300 mg (2.9 mmol) of (2R)-tetrahydrofuran-2-ylmethanol and 512 μl (3.0mmol, 1.05 eq.) of trifluoromethanesulphonic anhydride in the presenceof 369 μl (3.2 mmol, 1.1 eq.) of 2,6-dimethylpyridine were reactedaccording to General Method 8A. The crude product was reacted in thenext step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.35 (dd, 1H), 4.17 (dd, 1H), 4.09(dq, 1H), 3.86-3.70 (m, 2H), 2.00-1.79 (m, 3H), 1.61-1.47 (m, 1H).

Example 30.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2)

450 mg (purity 94%, 1.1 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.35 ml (1.35 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 396 mg (1.7 mmol, 1.5eq.) of (2R)-tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate werereacted according to General Method 7B. Yield: 625 mg (purity 76%, 92%of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=459 (M+H)⁺.

Example 30.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

625 mg (purity 76%, 1.0 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 585 mg (purity 73%,quant.)

LC/MS [Method 1]: diastereomer 1: R_(t)=2.33 min; MS (ESIpos): m/z=403(M+H)⁺; diastereomer 2: R_(t)=2.38 min; MS (ESIpos): m/z=403 (M+H)⁺.

Example 30.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

585 mg (purity 73%, 1.1 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2) and 225 mg(1.2 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted accordingto General Method 5A. Yield: 327 mg (53% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=578 (M+H)⁺.

Example 31.1A (2S)-Tetrahydrofuran-2-ylmethanol

Under argon and at 0° C., 3.3 ml (32.4 mmol, 1.8 eq.) of borane/dimethylsulphide complex were added dropwise to a solution of 2.13 g (18.0 mmol)of (2S)-tetrahydrofuran-2-carboxylic acid in 35 ml of dichloromethane,the reaction mixture was stirred at RT overnight and aqueous sodiumhydroxide solution (2M) was then added dropwise. After phase separation,the aqueous phase was extracted with dichloromethane. The combinedorganic phases were dried (sodium sulphate), filtered, concentratedunder reduced pressure and dried. Yield: 2.19 g (assumed purity of 80%,quant.)

Example 31.1B (2S)-Tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate

2.19 g (assumed purity of 80%, 17.2 mmol) of(2S)-tetrahydrofuran-2-ylmethanol and 3.1 ml (18.0 mmol, 1.05 eq.) oftrifluoromethanesulphonic anhydride in the presence of 2.2 ml (18.9mmol, 1.1 eq.) of 2,6-dimethylpyridine were reacted according to GeneralMethod 8A. The crude product was reacted in the next step withoutfurther purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.35 (dd, 1H), 4.17 (dd, 1H), 4.09(dq, 1H), 3.86-3.70 (m, 2H), 2.00-1.79 (m, 3H), 1.60-1.47 (m, 1H).

Example 31.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2,9-tetrahydrofuran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2)

3.0 g (purity 93%, 7.4 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 8.9 ml (8.9 mmol, 1.2 eq.) of bis(trimethylsilyl)lithiumamide (1M in THF) and 3.5 g (assumed purity 80%, 11.9 mmol, 1.6 eq.) of(2S)-tetrahydrofuran-2-ylmethyl trifluoromethanesulphonate were reactedaccording to General Method 7B. Yield: 1.7 g (49% of theory)

LC/MS [Method 8]: R_(t)=1.09 min; MS (ESIpos): m/z=403(M-tert.-Butyl+H)⁺.

Example 31.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

1.57 g (3.36 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 1.41 g (purity 92%, 96%of theory)

LC/MS [Method 8]: diastereomer 1: R_(t)=1.09 min; MS (ESIpos): m/z=403(M+H)⁺; diastereomer 2: R_(t)=1.11 min; MS (ESIpos): m/z=403 (M+H)⁺.

Example 31.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2,9-tetrahydrofuran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

1.54 g (purity 92%, 3.52 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2) and 747 mg(3.87 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 1.61 g (79% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=578 (M+H)⁺.

Example 32.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-hydroxy-3-(tetrahydrofuran-3-yl)propanoate(diastereomer mixture)

At −70° C., 6.94 ml (6.94 mmol, 1.3 eq.) of bis(trimethylsilyl)lithiumamide (1M in THF) were added dropwise to a solution of 2.00 g (5.34mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in50 ml of tetrahydrofuran, the mixture was stirred at −70° C. for 10 min,a solution of 801 mg (8.00 mmol, 1.5 eq.) oftetrahydrofuran-3-carbaldehyde in 4 ml of tetrahydrofuran was added andthe mixture was stirred at −70° C. for 90 min. The reaction mixture waswarmed to −20° C., and 25 ml of semisaturated aqueous ammonium chloridesolution were added. After phase separation, the aqueous phase wasextracted with diethyl ether. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered, concentrated under reduced pressure and dried. Thecrude product was purified by flash chromatography (KP-SIL, petroleumether/ethyl acetate 33-75%). Yield: 1.49 g (56% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=475 (M+H)⁺.

Example 32.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)acrylate(diastereomer mixture)

At RT, 0.5 ml (3.8 mmol, 1.2 eq.) of diethylaminosulphur trifluoride wasadded dropwise to a solution of 1.55 mg (3.13 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-hydroxy-3-(tetrahydrofuran-3-yl)propanoate(diastereomer mixture) in 48 ml of dichloromethane, the mixture wasstirred at RT for 90 min and 50 ml of dichloromethane and 50 ml ofsaturated aqueous sodium bicarbonate solution were then added. Afterphase separation, the aqueous phase was extracted with dichloromethane.The combined organic phases were washed with saturated aqueous sodiumchloride solution, dried (sodium sulphate), filtered, concentrated underreduced pressure and dried. Yield: 1.38 g (93% of theory)

LC/MS [Method 1]: R_(t)=1.03 min/1.05 min; MS (ESIpos): m/z=457(M+H)⁺/457 (M+H)⁺.

Example 32.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoate(mixture of racemic diastereomers)

At RT, 1.38 g (2.90 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)acrylate(diastereomer mixture) were admixed with 100 ml of a “Hot Stryker's”reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. Thereaction mixture was stirred at RT for 6 h and then concentrated underreduced pressure. Four times, the crude product was stirred with in eachcase 50 ml of acetonitrile and decanted. The combined organic phaseswere concentrated under reduced pressure. The residue was purified byflash chromatography (PF-50SIHC, petroleum ether/ethyl acetate 40-66%).Yield: 930 mg (70% of theory)

LC/MS [Method 1]: R_(t)=1.06 min; MS (ESIpos): m/z=459 (M+H)⁺.

Example 32.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoicacid (mixture of racemic diastereomers)

930 mg (2.0 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 6A. Yield: 974 mg (purity 94%, quant.)

LC/MS [Method 1]: R_(t)=0.77 min; MS (ESIpos): m/z=403 (M+H)⁺.

Example 32.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers)

900 mg (purity 94%, 2.1 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoicacid (mixture of racemic diastereomers) and 446 mg (2.3 mmol, 1.1 eq.)of tert-butyl 4-aminobenzoate were reacted according to General Method5A. Yield: 682 mg (purity 97%, 54% of theory) and 113 mg (purity 92%, 9%of theory)

LC/MS [Method 1]: R_(t)=1.20 min; MS (ESIpos): m/z=578 (M+H)⁺.

Example 33.1A Tetrahydro-2H-pyran-4-ylmethyl trifluoromethanesulphonate

5.00 g (43.0 mmol) of tetrahydro-2H-pyran-4-ylmethanol in 75 ml ofdichloromethane and 5.52 ml (47.3 mmol) of lutidine and 7.65 ml (45.2mmol) of trifluoromethanesulphonic anhydride were reacted according toGeneral Method 8A. The crude product was used for the next step withoutfurther purification. Yield: 12.4 g (quant.)

GC/MS [Method 9]: Rt=3.15 min; MS: m/z=248 (M)⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.37 (d, 2H), 4.03 (dd, 2H), 3.41 (dt,2H), 2.16-2.02 (m, 1H), 1.72-1.65 (m, 2H), 1.48-1.37 (m, 2H).

Example 33.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate(racemate)

1.65 g (4.41 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate,1.64 g (6.61 mmol) of tetrahydro-2H-pyran-4-ylmethyltrifluoromethanesulphonate and 5.73 ml (5.73 mmol) ofbis(trimethylsilyl)lithium amide (1M in THF) in 37 ml of THF werereacted according to General Method 7B. Purification by columnchromatography (80 g silica cartridge, flow rate: 60 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 1.57g (73% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=473 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.77-7.71 (m, 2H), 7.40(s, 1H), 6.51 (s, 1H), 5.32-5.26 (m, 1H), 3.85-3.76 (m, 2H), 3.64 (s,3H), 3.23-3.13 (m, 2H), 2.22-2.12 (m, 1H), 2.02-1.93 (m, 1H), 1.73-1.66(m, 1H), 1.51-1.45 (m, 1H), 1.40 (s, 9H), 1.36-1.13 (m, 3H).

Example 33.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoicacid (racemate)

1.57 g (3.32 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoate(racemate) in 25 ml of dichloromethane and 5.12 ml (66.4 mmol) of TFAwere reacted according to General Method 6A. Yield: 1.60 g (quant.)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=417 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (s, 1H), 7.99 (d, 1H), 7.77-7.71(m, 2H), 7.45 (s, 1H), 6.50 (s, 1H), 5.38-5.30 (m, 1H), 3.85-3.74 (m,2H), 3.63 (s, 3H), 3.22-3.12 (m, 2H), 2.26-2.16 (m, 1H), 2.05-1.96 (m,1H), 1.73-1.65 (m, 1H), 1.48-1.40 (m, 1H), 1.36-1.11 (3H).

Example 33.1D4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoicacid (racemate)

1.38 g (3.31 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoicacid (racemate), 547 mg (3.31 mmol) of ethyl 4-aminobenzoate, 471 mg(3.31 mmol) of Oxima and 516 μl (3.31 mmol) of DIC in 33 ml ofdimethylformamide were reacted according to General Method 5B. The crudeproduct was purified by flash chromatography (120 g cartridge, 85ml/min, cyclohexane/ethyl acetate gradient). Yield: 1.10 g (58% oftheory)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=564 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.00 (d, 1H), 7.94 (d,2H), 7.81-7.72 (m, 4H), 7.52 (s, 1H), 6.54 (s, 1H), 5.92-5.85 (m, 1H),4.33-4.25 (q, 2H), 3.87-3.77 (m, 2H), 3.69 (s, 3H), 3.25-3.11 (m, 2H),2.31-2.21 (m, 1H), 2.03-1.94 (m, 1H), 1.65-1.57 (m, 2H), 1.39-1.19 (m,3H), 1.32 (t, 3H).

Example 34.1A Tetrahydro-2H-pyran-3-ylmethyl trifluoromethanesulphonate(racemate)

232 mg (2.00 mmol) of tetrahydro-2H-pyran-3-ylmethanol and 355 μl (2.10mmol, 1.05 eq.) of trifluoromethanesulphonic anhydride in the presenceof 256 μl (2.20 mmol, 1.1 eq.) of 2,6-dimethylpyridine were reactedaccording to General Method 8A. The crude product was reacted in thenext step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.21-4.12 (m, 2H), 3.77 (dd, 1H),3.74-3.66 (m, 1H), 3.40-3.30 (m, 1H), 3.20 (dd, 1H), 2.00-1.87 (m, 1H),1.79-1.69 (m, 1H), 1.64-1.53 (m, 1H), 1.53-1.41 (m, 1H), 1.36-1.24 (m,1H).

Example 34.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoate(mixture of racemic diastereomers)

450 mg (purity 94%, 1.13 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.24 ml (1.24 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 467 mg (1.69 mmol, 1.5eq.) of tetrahydro-2H-pyran-3-ylmethyl trifluoromethanesulphonate(racemate) were reacted according to General Method 7B. Yield: 451 mg(purity 82%, 69% of theory)

LC/MS [Method 1]: R_(t)=1.13 min; MS (ESIpos): m/z=473 (M+H)⁺.

Example 34.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoicacid (mixture of racemic diastereomers)

451 mg (purity 82%, 0.78 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 6A. Yield: 440 mg (purity 82%, quant.)

LC/MS [Method 1]: racemic diastereomer 1: R_(t)=0.84 min; MS (ESIpos):m/z=417 (M+H)⁺; racemic diastereomer 2: R_(t)=0.86 min; MS (ESIpos):m/z=417 (M+H)⁺.

Example 34.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers)

440 mg (purity 82%, 0.87 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoicacid (mixture of racemic diastereomers) and 184 mg (0.95 mmol, 1.1 eq.)of tert-butyl 4-aminobenzoate were reacted according to General Method5A. Yield: 742 mg (purity 85%, quant.)

LC/MS [Method 1]: diastereomer 1: R_(t)=1.28 min; MS (ESIpos): m/z=592(M+H)+; diastereomer 2: R_(t)=1.29 min; MS (ESIpos): m/z=592 (M+H)⁺.

Example 35.1A Tetrahydro-2H-pyran-2-ylmethyl trifluoromethanesulphonate(racemate)

5.85 g (50.4 mmol) of tetrahydro-2H-pyran-2-ylmethanol in 88 ml ofdichloromethane and 6.45 ml (55.4 mmol) of lutidine and 8.95 ml (52.9mmol) of trifluoromethanesulphonic anhydride were reacted according toGeneral Method 8A. The crude product was used for the next step withoutfurther purification. Yield: 14.8 g (quant.)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.32 (dd, 1H), 4.18 (dd, 1H),3.96-3.93 (m, 1H), 3.59-3.52 (m, 1H), 3.47-3.40 (m, 1H), 1.84-1.74 (m,1H), 1.55-1.39 (m, 4H), 1.27-1.15 (m, 1H).

Example 35.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-2-yl)propanoate(mixture of racemic diastereomers)

4.20 g (11.2 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate,4.17 g (16.8 mmol) of tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate (racemate) and 11.8 ml (11.8 mmol) ofbis(trimethylsilyl)lithium amide (1M in THF) in 125 ml of THF werereacted according to General Method 7B. Purification by columnchromatography (100 g silica cartridge, flow rate: 50 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 2.6g (49% of theory)

LC/MS [Method 1]: R_(t)=1.21 min; MS (ESIpos): m/z=473 (M+H)⁺.

Example 35.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of racemic diastereomers)

2.50 g (5.29 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-2-yl)propanoate(mixture of racemic diastereomers) in 60 ml of dichloromethane and 15.3ml (198 mmol) of TFA were reacted according to General Method 6A. Yield:2.20 g (71% of theory)

LC/MS [Method 1]: R_(t)=0.93-0.94 min; MS (ESIpos): m/z=417 (M+H)⁺.

Example 35.1D Methyl({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate(mixture of racemic diastereomers)

2.20 g (5.28 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of racemic diastereomers), 798 mg (5.28 mmol) of methyl4-aminobenzoate, 750 mg (5.28 mmol) of Oxima and 822 μl (5.28 mmol) ofDIC in 110 ml of dimethylformamide were reacted according to GeneralMethod 5B. The reaction mixture was purified by flash chromatography (80g cartridge, 60 ml/min, cyclohexane/ethyl acetate gradient). Yield: 905mg (31% of theory)

LC/MS [Method 1]: R_(t)=1.14-1.16 min; MS (ESIpos): m/z=550 (M+H)⁺.

Example 36.1A 1,4-Dioxan-2-ylmethyl trifluoromethanesulphonate(racemate)

249 mg (2.00 mmol) of 1,4-dioxan-2-ylmethanol (racemate) and 355 μl(2.10 mmol, 1.05 eq.) of trifluoromethanesulphonic anhydride in thepresence of 256 μl (2.20 mmol, 1.1 eq.) of 2,6-dimethylpyridine werereacted according to General Method 8A. The crude product was reacted inthe next step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.35 (dd, 1H), 4.27 (dd, 1H),3.88-3.76 (m, 2H), 3.75-3.61 (m, 3H), 3.55-3.45 (m, 1H), 3.30 (t, 1H).

Example 36.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoate(mixture of racemic diastereomers)

346 mg (purity 93%, 0.86 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 0.95 ml (0.95 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 430 mg (purity 90%,1.55 mmol, 1.8 eq.) of 1,4-dioxan-2-ylmethyl trifluoromethanesulphonate(racemate) were reacted according to General Method 7B. Yield: 133 mg(33% of theory)

LC/MS [Method 1]: R_(t)=1.04 min; MS (ESIpos): m/z=475 (M+H)⁺.

Example 36.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoicacid (mixture of racemic diastereomers)

133 mg (0.28 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 6A. Yield: 132 mg (purity 60%, 68% of theory)

LC/MS [Method 8]: R_(t)=0.99 min; MS (ESIpos): m/z=419 (M+H)⁺.

Example 36.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers)

132 mg (purity 60%, 0.19 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoicacid (mixture of racemic diastereomers) and 40 mg (0.21 mmol, 1.1 eq.)of tert-butyl 4-aminobenzoate were reacted according to General Method5A. Yield: 106 mg (94% of theory)

LC/MS [Method 8]: racemic diastereomer 1: R_(t)=1.44 min; MS (ESIneg):m/z=592 (M−H)⁻; racemic diastereomer 2: R_(t)=1.46 min; MS (ESIneg):m/z=592 (M−H)⁻.

Example 37.1A 2-Fluoroethyl trifluoromethanesulphonate

At −78° C., a solution of 1.00 g (15.6 mmol) of 2-fluoroethanol and 2.39ml (17.2 mmol) of triethylamine in 5 ml of dichloromethane was addeddropwise to 2.89 ml (17.2 mmol) of trifluoromethanesulphonic anhydridein 5 ml of dichloromethane such that the internal temperature did notexceed −50° C. The mixture was stirred at −78° C. for another 15 min andspontaneously warmed to RT. The reaction mixture was diluted with 50 mlof methyl tert-butyl ether, washed three times with 25 ml of a mixtureof saturated aqueous sodium chloride solution/1N hydrochloric acid(3:1), dried over magnesium sulphate, filtered and concentrated at 25°C. and a pressure of ≧100 mbar. Yield: 2.3 g (75% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.78-4.74 (m, 1H), 4.66-4.62 (m, 1H),4.61-4.58 (m, 1H), 4.54-4.50 (m, 1H).

Example 37.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoate(racemate)

500 mg (1.26 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 445mg (2.27 mmol) of 2-fluoroethyl trifluoromethanesulphonate and 1.39 ml(1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml ofTHF were reacted according to General Method 7B. Purification by columnchromatography (120 g silica cartridge, flow rate: 80 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 360mg (67% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=421 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.75-7.72 (m, 2H), 7.44(s, 1H), 6.51 (s, 1H), 5.17 (dd, 1H), 4.66-4.49 (m, 1H), 4.44-4.27 (m,1H), 3.63 (s, 3H), 2.62-2.40 (m, 2H), 1.40 (s, 9H).

Example 37.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoicacid (racemate)

359 mg (853 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoate(racemate) in 8.5 ml of dichloromethane and 2.5 ml (32 mmol) of TFA werereacted according to General Method 6A. Yield: 306 mg (96% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIneg): m/z=363 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (s, 1H), 7.99 (d, 1H), 7.74 (s,1H), 7.73 (dd, 1H), 7.49 (s, 1H), 6.50 (s, 1H), 5.22 (dd, 1H), 4.66-4.48(m, 1H), 4.42-4.24 (m, 1H), 3.63 (s, 3H), 2.65-2.42 (m, 2H).

Example 37.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoyl}amino)benzoate(racemate)

100 mg (274 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoicacid (racemate), 53.0 mg (274 μmol) of tert-butyl 4-aminobenzoate, 39.0mg (274 μmol) of Oxima and 43.0 μl (274 μmol) of DIC in 5 ml ofdimethylformamide were reacted according to General Method 5B.Filtration gave the title compound. Yield: 117 mg (78% of theory)

LC/MS [Method 1]: R_(t)=1.20 min; MS (ESIpos): m/z=540 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.87 (d,2H), 7.77-7.73 (m, 4H), 7.51 (s, 1H), 6.55 (s, 1H), 5.85 (t, 1H),4.67-4.49 (m, 1H), 4.47-4.28 (m, 1H), 3.69 (s, 3H), 2.69-2.55 (m, 2H),1.54 (s, 9H).

Example 38.1A 2,2-Difluoroethyl trifluoromethanesulphonate

At −78° C., a solution of 1.00 g (12.2 mmol) of 2,2-difluoroethanol and1.87 ml (13.4 mmol) of triethylamine in 5 ml of dichloromethane wasadded dropwise to 2.26 ml (13.4 mmol) of trifluoromethanesulphonicanhydride in 5 ml of dichloromethane such that the internal temperaturedid not exceed −50° C. The mixture was stirred at −78° C. for another 15min and spontaneously warmed to RT. The reaction mixture was dilutedwith 50 ml of methyl tert-butyl ether and washed three times with 25 mlof a mixture of saturated aqueous sodium chloride solution/1Nhydrochloric acid (3:1), dried over magnesium sulphate, filtered andconcentrated at 25° C. and a pressure of ≧100 mbar. Yield: 1.48 g (51%of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=6.05 (tt, 1H), 4.59 (dt, 2H).

Example 38.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoate(racemate)

150 mg (388 μmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 125mg (582 μmol) of 2,2-difluoroethyl trifluoromethanesulphonate and 427 μl(427 μmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 3 ml ofTHF were reacted according to General Method 7B. Purification by columnchromatography (24 g silica cartridge, flow rate: 35 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 122mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=439 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.74-7.70 (m, 2H), 7.50(s, 1H), 6.52 (s, 1H), 6.19 (tt, 1H), 5.29-5.20 (m, 1H), 3.64 (s, 3H),2.83-2.65 (m, 2H), 1.39 (s, 9H).

Example 38.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoicacid (racemate)

114 mg (260 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoate(racemate) in 8 ml of dichloromethane and 400 μl (5.20 mmol) of TFA werereacted according to General Method 6A. Yield: 99 mg (91% of theory)

LC/MS [Method 1]: R_(t)=0.85 min; MS (ESIneg): m/z=381 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.4 (s, 1H), 7.99 (d, 1H), 7.73 (dd,1H), 7.72 (s, 1H), 7.55 (s, 1H), 6.51 (s, 1H), 6.18 (tt, 1H), 5.31-5.25(m, 1H), 3.63 (s, 3H), 2.83-2.65 (m, 2H).

Example 38.1D Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoyl}amino)benzoate(racemate)

97.0 mg (253 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoicacid (racemate), 42.0 mg (253 μmol) of ethyl 4-aminobenzoate, 36.0 mg(253 μmol) of Oxima and 39.0 μl (253 μmol) of DIC in 2.5 ml ofdimethylformamide were reacted according to General Method 5B. The crudeproduct was purified by preparative HPLC [column: Chromatorex C18, 10μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 81.7 mg (60% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=530 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.94 (d,2H), 7.76 (d, 2H), 7.75-7.71 (m, 2H), 7.56 (s, 1H), 6.55 (s, 1H), 6.15(tt, 1H), 5.90 (dd, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 2.97-2.78 (m, 2H),1.31 (t, 3H).

Example 39.1A 2,2,2-Trifluoroethyl trifluoromethanesulphonate

At −78° C., a solution of 1.00 g (10.0 mmol) of 2,2,2-trifluoroethanoland 1.53 ml (11.0 mmol) of triethylamine in 5 ml of dichloromethane wasadded dropwise to 1.85 ml (11.0 mmol) of trifluoromethanesulphonicanhydride in 5 ml of dichloromethane such that the internal temperaturedid not exceed −50° C. The mixture was stirred at −78° C. for another 15min and spontaneously warmed to RT. The reaction mixture was dilutedwith 50 ml of methyl tert-butyl ether and washed three times with 25 mlof a mixture of saturated aqueous sodium chloride solution/1Nhydrochloric acid (3:1), dried over magnesium sulphate, filtered andconcentrated at 25° C. and a pressure of ≧100 mbar. Yield: 1.0 g (43% oftheory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.71 (q, 2H).

Example 39.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoate(racemate)

500 mg (1.29 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 360mg (1.55 mmol) of 2,2,2-trifluoromethyl trifluoromethanesulphonate and1.42 ml (1.42 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in10 ml of THF were reacted according to General Method 7B. Purificationby column chromatography (24 g silica cartridge, flow rate: 35 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 66mg (11% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=457 (M+H)⁺.

Example 39.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoicacid (racemate)

65.0 mg (142 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoate(racemate) in 1.6 ml of dichloromethane and 411 μl (5.34 mmol) of TFAwere reacted according to General Method 6A. Yield: 53 mg (81% oftheory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=401 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.5 (br. s, 1H), 7.99 (d, 1H),7.74-7.72 (m, 2H), 7.59 (s, 1H), 6.52 (s, 1H), 5.43-5.38 (m, 1H), 3.63(s, 3H), 3.33-3.14 (m, 2H).

Example 39.1D Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoyl}amino)benzoate(racemate)

63.0 mg (157 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoicacid (racemate), 26.0 mg (157 μmol) of ethyl 4-aminobenzoate, 22.3 mg(157 μmol) of Oxima and 24.0 μl (157 μmol) of DIC in 1.6 ml ofdimethylformamide were reacted according to General Method 5B. Thereaction product was purified by preparative HPLC [column: ChromatorexC18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acidgradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and afurther 3 min 90% acetonitrile)]. Yield: 25.1 mg (28% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=548 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.00 (d, 1H), 7.95 (d,2H), 7.78 (d, 2H), 7.74 (dd, 1H), 7.72 (s, 1H), 7.62 (s, 1H), 6.56 (s,1H), 6.11-6.03 (m, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 3.57-3.44 (m, 1H),3.38-3.26 (m, 1H), 1.31 (t, 3H).

Example 40.1A 2-Fluoropropyl trifluoromethanesulphonate (racemate)

156 mg (1.94 mmol) of 2-fluoropropan-1-ol and 361 μl (2.13 mmol, 1.1eq.) of trifluoromethanesulphonic anhydride in the presence of 297 μl(2.13 mmol, 1.1 eq.) of triethylamine were reacted according to GeneralMethod 8A. The crude product was reacted in the next step withoutfurther purification.

Example 40.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoate(mixture of racemic diastereomers)

450 mg (purity 94%, 1.13 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.24 ml (1.24 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 356 mg (1.69 mmol, 1.5eq.) of 2-fluoropropyl trifluoromethanesulphonate (racemate) werereacted according to General Method 7B. Yield: 270 mg (52% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=435 (M+H)⁺.

Example 40.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoicacid (mixture of racemic diastereomers)

270 mg (0.59 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 6A. Yield: 222 mg (purity 85%, 84% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=379 (M+H)⁺.

Example 40.1D Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoyl}amino)benzoate(mixture of racemic diastereomers)

222 mg (purity 85%, 0.50 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoicacid (mixture of racemic diastereomers) and 91 mg (0.55 mmol, 1.1 eq.)of ethyl 4-aminobenzoate were reacted according to General Method 5A.Yield: 180 mg (purity 91%, 63% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=526 (M+H)⁺.

Example 41.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,4,5-trideoxy-5,5,5-trifluoro-4-methylpentonate(diastereomer mixture)

At −70° C., 1.17 ml (1.17 mmol, 1.1 eq.) of bis(trimethylsilyl)lithiumamide (1M in THF) were added dropwise to a solution of 400 mg (1.07mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in10.8 ml of tetrahydrofuran, the mixture was stirred at −70° C. for 10min, a solution of 175 mg (1.39 mmol, 1.3 eq.) of2-(trifluoromethyl)propionaldehyde in 0.8 ml of tetrahydrofuran wasadded and the mixture was stirred at −70° C. for 1 h. The reactionmixture was warmed to RT and stirred at RT for a further 30 min, and 5ml of saturated aqueous ammonium chloride solution were added. Afterphase separation, the aqueous phase was extracted twice with ethylacetate. The combined organic phases were washed with saturated aqueoussodium chloride solution, dried (sodium sulphate), filtered,concentrated under reduced pressure and dried. The crude product waspurified by flash chromatography (KP-SIL, ethyl acetate/cyclohexane20-50%). Yield: 274 mg (purity 75%, 38% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=501 (M+H)⁺.

Example 41.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpent-2-enate(diastereomer mixture)

At RT, 64 μl (0.48 mmol, 1.2 eq.) of diethylaminosulphur trifluoridewere added dropwise to a solution of 270 mg (0.40 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-2,4,5-trideoxy-5,5,5-trifluor-4-methylpentonate(diastereomer mixture) in 6 ml of dichloromethane, the mixture wasstirred at RT for 90 min and 3 ml of dichloromethane and 6 ml ofsaturated aqueous sodium bicarbonate solution were then added. Afterphase separation, the aqueous phase was extracted with ethyl acetate.The combined organic phases were washed with saturated aqueous sodiumchloride solution, dried (sodium sulphate), filtered, concentrated underreduced pressure and dried. Yield: 224 mg (purity 72%, 83% of theory)

LC/MS [Method 2]: R_(t)=3.78 min; MS (ESIpos): m/z=483 (M+H)⁺.

Example 41.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoate(mixture of racemic diastereomers)

At RT, 193 mg (purity 72%, 0.29 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpent-2-enoate(diastereomer mixture) were admixed with 10 ml of a “Hot Stryker's”reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292], andthe reaction mixture was stirred at RT for 6 h. After addition of afurther 8 ml of a “Hot Stryker's” reagent solution, the reaction mixturewas stirred at RT overnight and then concentrated under reducedpressure. Three times, the crude product was stirred with in each case15 ml of acetonitrile and decanted. The combined organic phases wereconcentrated under reduced pressure. The residue was purified by flashchromatography (KP-SIL, ethyl acetate/cyclohexane 20-33%). Yield: 169 mg(purity 92%, quant.)

LC/MS [Method 1]: R_(t)=1.21 min; MS (ESIpos): m/z=485 (M+H)⁺.

Example 41.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluor-4-methylpentanoicacid (mixture of racemic diastereomers)

190 mg (purity 92%, 0.36 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluor-4-methylpentanoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 6A. The crude product was reacted in the next stepwithout further purification. Yield: 129 mg

Example 41.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoyl}amino)benzoate(mixture of racemic diastereomers)

129 mg of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoicacid (mixture of racemic diastereomers) and 59 mg (0.31 mmol, 1.1 eq.)of tert-butyl 4-aminobenzoate were reacted according to General Method5A. Yield: 51 mg (30% of theory)

LC/MS [Method 1]: R_(t)=1.37 min; MS (ESIpos): m/z=604 (M+H)⁺.

Example 42.1A 2-Hydroxy-4,4-dimethylpentanoic acid (racemate)

805 mg (5.54 mmol) of 4-methylleucine (racemate) were initially chargedin 11 ml of sulphuric acid (1M) and cooled to 0° C. 2.30 g (33.3 mmol)of sodium nitrite as a solution in 6.5 ml of water were then slowlyadded dropwise over a period of 90 min. The solution was stirred at RTfor another 24 h. The mixture was carefully diluted with 10 ml of waterand the aqueous phase was extracted five times with 10 ml of methyltert-butyl ether. The combined organic phases were washed with 25 ml ofsaturated aqueous sodium chloride solution, dried over sodium sulphateand filtered, and the solvent was removed under reduced pressure. Thecrude product was used for the next step without further purification.Yield: 667 mg (82% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.99 (dd, 1H), 1.56 (dd, 1H), 1.40(dd, 1H), 0.93 (s, 9H).

Example 42.1B Benzyl 2-hydroxy-4,4-dimethylpentanoate (racemate)

743 mg (2.28 mmol) of caesium carbonate were added to a solution of 667mg (4.56 mmol) of 2-hydroxy-4,4-dimethylpentanoic acid (racemate) in 8.7ml of methanol and 1.7 ml of water The reaction mixture was stirred atRT for 60 min and the solvent was then removed under reduced pressure.The residue was dried under high vacuum (4 h) and then taken up in 10 mlof dimethylformamide. At 0° C., 516 μl (4.33 mmol) of benzyl bromidewere slowly added dropwise. The reaction mixture was stirred at RT for12 h, the reaction was terminated by addition of 25 ml of water and thereaction mixture was extracted three times with 20 ml of ethyl acetate.The combined organic phases were dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (40 g silica cartridge, 35ml/min, cyclohexane/ethyl acetate gradient). Yield: 584 mg (54% oftheory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=7.39-7.33 (m, 5H), 5.23 (d, 1H), 5.18(d, 1H), 4.29 (ddd, 1H), 2.62 (d, 1H), 1.73 (dd, 1H), 1.49 (dd, 1H),0.99 (s, 9H).

Example 42.1C Benzyl4,4-dimethyl-2-{[(trifluoromethyl)sulphonyl]oxy}pentanoate (racemate)

236 mg (1.00 mmol) of benzyl 2-hydroxy-4,4-dimethylpentanoate (racemate)in 10 ml of dichloromethane and 175 μl (1.50 mmol) of lutidine and 254μl (1.50 mmol) of trifluoromethanesulphonic anhydride were reactedaccording to General Method 8A. The crude product was used for the nextstep without further purification. Yield: 365 mg (99% of theory)

Example 42.1D Benzyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoate

A little at a time, 41.8 mg (1.04 mmol) of sodium hydride (60% inmineral oil) were added to a suspension of 261 mg (purity 87%, 870 μmol)of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in10 ml of THF, and the mixture was stirred at RT for another 1 h. 481 mg(1.31 mmol) of benzyl4,4-dimethyl-2-{[(trifluoromethyl)sulphonyl]oxy}pentanoate (racemate) asa solution in 3 ml of THF were quickly added dropwise to the resultingreaction solution, and after the addition had ended the mixture wasstirred at RT for another 1.5 h. The reaction was terminated by additionof 10 ml of saturated aqueous ammonium chloride solution and 15 ml ofmethyl tert-butyl ether. The phases were separated and the aqueous phasewas extracted three times with 10 ml of methyl tert-butyl ether. Thecombined organic phases were dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The crude productwas purified by flash chromatography (80 g silica cartridge, 60 ml/min,cyclohexane/ethyl acetate gradient). Yield: 294 mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.29 min; MS (ESIpos): m/z=479 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.74-7.70 (m, 2H), 7.55(s, 1H), 7.39-7.30 (m, 5H), 6.53 (s, 1H), 5.56-5.50 (m, 1H), 5.18 (s,2H), 3.63 (s, 3H), 2.19-2.10 (m, 2H), 0.87 (s, 9H).

Example 42.1E2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoicacid

17.5 mg (438 μmol, 60% in mineral oil) of sodium hydride were added to asolution of 140 mg (292 μmol) of benzyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoate(racemate) in 5 ml of THF (not dry), and the mixture was stirred foranother 15 min. The reaction was terminated by addition of 5 ml ofsaturated aqueous ammonium chloride solution, 10 ml of dichloromethaneand 0.5 ml of hydrochloric acid (1N). The phases were separated and theaqueous phase was extracted three times with 5 ml of dichloromethane.The combined organic phases were dried over sodium sulphate andfiltered, and the solvent was removed under reduced pressure. Theresidue corresponded to the title compound and was used for the nextstep without further purification. Yield: 110 mg (83% of theory, purity86%)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIneg): m/z=387 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (s, 1H), 7.97 (d, 1H), 7.73 (s,1H), 7.72 (dd, 1H), 7.52 (s, 1H), 6.48 (s, 1H), 5.50-5.38 (br. s, 1H),3.65 (s, 3H), 2.16-2.10 (m, 2H), 0.86 (s, 9H).

Example 42.1F tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoyl}amino)benzoate(racemate)

110 mg (283 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoicacid (racemate), 65.6 mg (339 μmol) of tert-butyl 4-aminobenzoate, 129mg (339 μmol) of HATU and 148 μl (849 μmol) of N,N-diisopropylethylaminein 9 ml of dimethylformamide were reacted according to General Method5A. The solvent was removed and the residue was purified by preparativeHPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase:acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield:100 mg (62% of theory)

LC/MS [Method 4]: R_(t)=2.90 min; MS (ESIpos): m/z=564 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 7.99 (d, 1H), 7.88 (d,2H), 7.77 (d, 2H), 7.74-7.71 (m, 2H), 7.60 (s, 1H), 6.53 (s, 1H), 5.98(dd, 1H), 3.70 (s, 3H), 2.14 (dd, 1H), 2.02 (dd, 1H), 1.54 (s, 9H), 0.92(s, 9H).

Example 43.1A 2,2-Difluorocyclopropanecarbaldehyde

484 μl (5.55 mmol) of oxalyl chloride with 4A molecular sieve wereinitially charged in 5 ml of dichloromethane, and the mixture was cooledto −78° C. At −78° C., 410 μl (5.78 mmol) of DMSO were added dropwise,and the mixture was stirred for another 5 min. A solution of 500 mg(4.63 mmol) of 2,2-difluorocyclopropanemethanol in 5 ml ofdichloromethane was then added, and the mixture was stirred at −78° C.for 30 min. After addition of 1.93 ml (13.9 ml) of triethylamine, thereaction solution was stirred at RT for another 10 min and then dilutedwith 30 ml of water and 30 ml of dichloromethane. The phases wereseparated and the aqueous phase was extracted twice with 50 ml ofdichloromethane. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. The crudeproduct was used for the next step without further purification.

Example 43.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2,2-difluorocyclopropyl)prop-2-enoate(diastereomer mixture)

At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1Min THF) were added dropwise to a solution of 500 mg (1.33 mmol) oftert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in10 ml of THF, and the mixture was stirred for another 10 min 488 mg(4.60 mmol) of 2,2-difluorocyclopropanecarbaldehyde were then added, andafter a further 10 min the mixture was warmed to −20° C. After 3 h at−20° C., the reaction was terminated by addition of 30 ml of saturatedaqueous ammonium chloride solution and the reaction mixture wasextracted three times with 20 ml of ethyl acetate. The combined organicphases were washed with saturated aqueous sodium chloride solution,dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was taken up in a littledichloromethane and purified by flash chromatography (24 g silicacartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 240 mg(purity 78%, 30% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=463 (M+H)⁺.

Example 43.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoate(mixture of two racemic diastereomers)

At RT, 240 mg (purity 78%, 404 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(2,2-difluorocyclopropyl)prop-2-enoate(diastereomer mixture) were admixed with 30 ml of a “Hot Stryker's”reagent solution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. Thereaction mixture was stirred at RT for 2 h, and 20 ml of saturatedaqueous ammonium chloride solution were then added. The phases wereseparated and the aqueous phase was extracted three times with 25 ml ofethyl acetate. The combined organic phases were dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The residue was purified by flash chromatography (40 g silicacartridge, 40 ml/min, cyclohexane/ethyl acetate gradient). Yield: 216 mg(quant.)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=465 (M+H)⁺.

Example 43.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoicacid (mixture of two racemic diastereomers)

216 mg (465 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoate(mixture of two racemic diastereomers) in 1 ml of dichloromethane and537 μl (6.97 mmol) of TFA were reacted according to General Method 6A.The crude product was purified by preparative HPLC [column: ChromatorexC18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.1% formic acidgradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and afurther 3 min 90% acetonitrile)]. Yield: 88 mg (44% of theory)

LC/MS [Method 1]: R_(t)=0.86/0.88 min; MS (ESIpos): m/z=409 (M+H)⁺.

Example 43.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoate(mixture of two racemic diastereomers)

88.0 mg (215 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoicacid (mixture of two racemic diastereomers), 41.6 mg (215 μmol) oftert-butyl 4-aminobenzoate, 30.6 mg (215 μmol) of Oxima and 34.0 μl (215μmol) of DIC in 2.1 ml of dimethylformamide were reacted according toGeneral Method 5B. Yield: 101 mg (66% of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=584 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8/10.7 (2×s, 1H), 8.00 (d, 1H),7.90-7.85 (m, 2H), 7.77-7.71 (m, 4H), 7.53 (s, 1H), 6.55 (s, 1H),5.80-5.69 (m, 1H), 3.70/3.69 (2×s, 3H), 2.63-2.38 (m, 1H), 2.34-2.07(2×m, 1H), 1.71-1.46 (m, 2H), 1.54 (s, 9H), 1.35-1.04 (2×m, 1H).

Example 44.1A 1-Methylcyclopropanecarbaldehyde

608 μl (6.97 mmol) of oxalyl chloride with 4A molecular sieve wereinitially charged in 5 ml of dichloromethane, and the mixture was cooledto −78° C. At −78° C., 515 μl (7.26 mmol) of DMSO were added dropwise,and the mixture was stirred for another 5 min. A solution of 500 mg(5.81 mmol) of (1-methylcyclopropyl)methanol in 5 ml of dichloromethanewas then added, and the mixture was stirred at −78° C. for 30 min. Afteraddition of 2.43 ml (17.4 ml) of triethylamine, the reaction solutionwas stirred at RT for another 10 min and then diluted with 30 ml ofwater and 30 ml of dichloromethane. The phases were separated and theaqueous phase was extracted twice with 50 ml of dichloromethane. Thecombined organic phases were washed with saturated aqueous sodiumchloride solution, dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude product was usedfor the next step without further purification.

Example 44.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)prop-2-enoate(isomer mixture)

At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1Min THF) were added dropwise to a solution of 500 mg (1.33 mmol) oftert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in10 ml of THF, and the mixture was stirred for another 10 min 488 mg(5.80 mmol) of 1-methylcyclopropanecarbaldehyde were then added, andafter a further 10 min the mixture was warmed to −20° C. After 3 h at−20° C., the reaction was terminated by addition of 30 ml of saturatedaqueous ammonium chloride solution and the reaction mixture wasextracted three times with 20 ml of ethyl acetate. The combined organicphases were washed with saturated aqueous sodium chloride solution,dried over magnesium sulphate and filtered, and the solvent was removedunder reduced pressure. The residue was taken up in a littledichloromethane and purified by flash chromatography (24 g silicacartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 257 mg(44% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=441 (M+H)⁺.

Example 44.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoate(racemate)

At RT, 257 mg (583 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)prop-2-enoate(isomer mixture) were admixed with 30 ml of a “Hot Stryker's” reagentsolution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reactionmixture was stirred at RT for 2 h, and 20 ml of saturated aqueousammonium chloride solution were then added. The phases were separatedand the aqueous phase was extracted three times with 25 ml of ethylacetate. The combined organic phases were dried over magnesium sulphateand filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (40 g silica cartridge, 35ml/min, cyclohexane/ethyl acetate gradient). Yield: 247 mg (96% oftheory)

LC/MS [Method 1]: R_(t)=1.21 min; MS (ESIpos): m/z=443 (M+H)⁺.

Example 44.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoicacid (racemate)

247 mg (558 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoate(racemate) in 1 ml of dichloromethane and 859 μl (11.2 mmol) of TFA werereacted according to General Method 6A. The crude product was purifiedby preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobilephase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90%acetonitrile)]. Yield: 95 mg (43% of theory)

LC/MS [Method 2]: R_(t)=2.70 min; MS (ESIpos): m/z=387 (M+H)⁺.

Example 44.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoyl}amino)benzoate(racemate)

95.0 mg (246 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoicacid (racemate), 47.5 mg (246 μmol) of tert-butyl 4-aminobenzoate, 34.9mg (246 μmol) of Oxima and 38.3 μl (246 μmol) of DIC in 2.5 ml ofdimethylformamide were reacted according to General Method 5B. Yield:101 mg (66% of theory)

LC/MS [Method 1]: R_(t)=1.32 min; MS (ESIpos): m/z=562 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.88 (d,2H), 7.77 (d, 2H), 7.75-7.72 (m, 2H), 7.54 (s, 1H), 6.53 (s, 1H), 5.97(dd, 1H), 3.68 (s, 3H), 2.20 (dd, 1H), 2.05 (dd, 1H), 1.54 (s, 9H), 1.07(s, 3H), 0.35-0.25 (m, 2H), 0.21-0.12 (m, 2H).

Example 45.1A Ethyl 3-cyclobutyl-2-hydroxypropanoate (racemate)

359 mg (14.8 mmol, 1.1 eq.) of magnesium turnings were covered withdiethyl ether and etched by addition of a small piece of iodine for 3-4min. Under argon and at RT, 5 ml of a solution of 2.0 g (13.4 mmol) of(bromomethyl)cyclobutane in 30 ml of diethyl ether were added withstirring to this mixture, the reaction was stirred for 5 min (until thereaction is initiated) and the remainder of the(bromomethyl)cyclobutane/diethyl ether solution is added dropwise over afurther 10 min. The reaction mixture was stirred under reflux for 1 h,cooled under a stream of argon and, with ice-water cooling, addeddropwise to a solution of 2.4 ml (12.1 mmol, 0.9 eq.) of ethylglyoxylate (50% in toluene). The reaction mixture was stirred at RT for1 h, carefully quenched to pH 7 with 20 ml of a potassium citrate/citricacid solution (pH 5) and then adjusted to pH 4-5 with aqueoushydrochloric acid (1N). After phase separation, the aqueous phase wasextracted with diethyl ether. The combined organic phases were dried(sodium sulphate), filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel 50, mobilephase: cyclohexane/ethyl acetate 20%-33%). Yield: 110 mg (purity 94%, 5%of theory)

LC/MS [Method 8]: R_(t)=3.37 min; MS (ESIpos): m/z=172 (M)⁺.

Example 45.1B Ethyl3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate (racemate)

110 mg (purity 94%, 0.60 mmol) of ethyl 3-cyclobutyl-2-hydroxypropanoate(racemate) and 142 μl (0.84 mmol, 1.4 eq.) of trifluoromethanesulphonicanhydride in the presence of 105 μl (0.90 mmol, 1.5 eq.) of2,6-dimethylpyridine were reacted according to General Method 8A. Thecrude product was reacted in the next step without further purification.

Example 45.1C Ethyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoate(racemate)

122 mg (purity 87%, 0.41 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in thepresence of 1.3 eq. of sodium hydride and 161 mg (0.53 mmol, 1.3 eq.) ofethyl 3-cyclobutyl-2-{[(trifluoromethyl)sulphonyl]oxy}propanoate(racemate) were reacted at RT according to General 4E. The crude productwas purified by flash chromatography (KP-SIL, cyclohexane/ethyl acetate15-33%). Yield: 140 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=415 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.78-7.69 (m, 2H), 7.42(s, 1H), 6.48 (s, 1H), 5.12 (dd, 1H), 4.21-4.07 (m, 2H), 3.64 (s, 3H),2.38-2.24 (m, 1H), 2.23-2.11 (m, 2H), 2.05-1.93 (m, 1H), 1.89-1.61 (m,4H), 1.60-1.47 (m, 1H), 1.18 (t, 3H).

Example 45.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoicacid (racemate)

138 mg (0.33 mmol) of ethyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 104 mg (82% of theory)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIpos): m/z=387 (M+H)⁺.

Example 45.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)benzoate(racemate)

104 mg (0.27 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoicacid (racemate) and 57 mg (0.30 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 66mg (purity 86%, 38% of theory)

LC/MS [Method 1]: R_(t)=1.38 min; MS (ESIpos): m/z=562 (M+H)⁺.

Example 46.1A Ethyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetate(racemate)

Under argon and at 0° C., 10 min apart two portions of in total 350 mg(purity 82%, 1.10 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile wereadded to a suspension of 53 mg (1.32 mmol, 1.2 eq.) of sodium hydride(60% in mineral oil) in 2.1 ml of dimethylformamide. The reactionmixture was stirred at RT for 60 min and then cooled back to 0° C., 245mg (purity 90%, 1.32 mmol, 1.2 eq.) of ethyl 2-chloro-2-ethoxyacetatewere added and the mixture was stirred at RT for 2 h. This batchtogether with an analogous test batch was combined with 50 mg (purity82%, 0.16 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile. Afteraddition of 20 ml of water and phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography(IR-50Si, petroleum ether/ethyl acetate 15-50%). Yield: 277 mg (55% oftheory based on in total 1.26 mmol of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrileemployed)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=391 (M+H)⁺.

Example 46.1B[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)aceticacid (racemate)

277 mg (0.69 mmol) of ethyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 180 mg (71% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=363 (M+H)⁺.

Example 46.1C tert-Butyl4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetyl}amino)benzoate(racemate)

180 mg (0.50 mmol) of[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)aceticacid (racemate) and 105 mg (0.55 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 265mg (quant.)

LC/MS [Method 1]: R_(t)=1.22 min; MS (ESIpos): m/z=538 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.74 (s, 1H), 8.01 (d, 1H), 7.90 (d,2H), 7.80 (d, 2H), 7.79-7.71 (m, 2H), 7.35 (s, 1H), 6.57 (s, 1H), 6.40(s, 1H), 3.82-3.72 (m, 1H), 3.72-3.60 (m, 1H), 3.67 (s, 3H), 1.54 (s,9H), 1.27 (t, 3H).

Example 47.1A[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid

187 mg (500 μmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and770 μl (10.0 mmol) of TFA were reacted according to General Method 6A.Yield: 159 mg (93% of theory)

LC/MS [Method 1]: R_(t)=0.72 min; MS (ESIneg): m/z=317 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (s, 1H), 8.00 (d, 1H), 7.74 (dd,1H), 7.72 (s, 1H), 7.58 (s, 1H), 6.51 (s, 1H), 4.64 (s, 2H), 3.62 (s,3H).

Example 47.1B tert-Butyl4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)benzoate

159 mg (499 μmol) of[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetic acid,116 mg (599 μmol) of tert-butyl 4-aminobenzoate, 228 mg (599 μmol) ofHATU and 261 μl (1.50 mmol) of N,N-diisopropylethylamine in 8 ml ofdimethylformamide were reacted according to General Method 5A. Thesolvent was removed and the residue was purified by preparative HPLC[column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase:acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield:54.5 mg (22% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=494 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.7 (s, 1H), 8.00 (d, 1H), 7.88 (d,2H), 7.75-7.71 (m, 4H), 7.60 (s, 1H), 6.52 (s, 1H), 4.81 (s, 2H), 3.64(s, 3H), 1.54 (s, 9H).

Example 48.1A Methyl4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (trans/cismixture)

5.0 g (32 mmol) of methyl 4-hydroxycyclohexanecarboxylate were initiallycharged in 100 ml of dimethylformamide. 6.7 g (44 mmol) oftert-butyldimethylsilyl chloride and 4.1 g (60 mmol) of imidazole werethen added, and the mixture was stirred at RT for another 14 h. Thesolvent was removed under reduced pressure and the residue was taken upin 100 ml of methyl tert-butyl ether and 100 ml of saturated aqueoussodium bicarbonate solution. The phases were separated, the organicphase was dried over magnesium sulphate and filtered and the solvent wasremoved under reduced pressure. Yield: 8.1 g (93% of theory)

GC/MS [Method 9]: R_(t)=4.79 min; MS: m/z=272 (M)⁺.

Example 48.1B (4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methanol(trans/cis mixture)

At 0° C., 8.1 g (29.7 mmol) of methyl4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (trans/cismixture) as a solution in 50 ml of THF were added dropwise to a solutionof 50 ml (100 mmol) of lithium aluminium hydride (2M in THF). Themixture was stirred at 0° C. for another 1 h and at RT for another 2 h.3.8 ml of water, 3.8 ml of aqueous sodium hydroxide solution (15%) and11.4 ml of water were then added to the reaction in succession, and theprecipitate was filtered off. The organic phase was washed with 50 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. Yield: 7.00 g (92% of theory)

GC/MS [Method 9]: R_(t)=4.74 min; MS: m/z=244 (M)⁺.

Example 48.1C (4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)methyltrifluoromethanesulphonate (trans/cis mixture)

1.00 g (4.09 mmol) of(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methanol (trans/cismixture) in 25 ml of dichloromethane were reacted with 715 μl (6.14mmol) of lutidine and 1.04 ml (6.14 mmol) of trifluoromethanesulphonicanhydride according to General Method 8A. The crude product was used forthe next step without further purification. Yield: 1.47 g (91% oftheory)

Example 48.1D tert-Butyl 3-(4-[tert-butyl(dimethyl)silyl]oxycyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoate(mixture of two racemic diastereomers)

500 mg (1.26 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 712mg (1.89 mmol) of (4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)methyltrifluoromethanesulphonate (trans/cis mixture) and 1.39 ml (1.39 mmol)of bis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF werereacted according to General Method 7B. Purification by columnchromatography (120 g silica cartridge, flow rate: 85 ml/min,cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 479mg (63% of theory)

LC/MS [Method 1]: R_(t)=1.56/1.59 min; MS (ESIpos): m/z=601 (M+H)⁺.

Example 48.1E3-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (mixture of two racemic diastereomers)

479 mg (797 μmol) of tert-butyl3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoate(mixture of two racemic diastereomers) were reacted with 4 ml of aqueouslithium hydroxide solution (1N) according to General Method 6B, givingthe title compound. Yield: 400 mg (80% of theory)

LC/MS [Method 1]: R_(t)=1.36/1.39 min; MS (ESIpos): m/z=545 (M+H)⁺.

Example 48.1F tert-Butyl4-({3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(mixture of two racemic diastereomers)

400 mg (734 μmol) of3-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoicacid (mixture of two racemic diastereomers), 142 mg (734 μmol) oftert-butyl 4-aminobenzoate, 104 mg (734 μmol) of Oxima and 114 μl (734μmol) of DIC in 7.3 ml of dimethylformamide were reacted according toGeneral Method 5B. The crude product was purified by flashchromatography (40 g cartridge, 40 ml/min, cyclohexane/ethyl acetategradient). Yield: 341 mg (64% of theory)

LC/MS [Method 1]: R_(t)=1.61/1.64 min; MS (ESIpos): m/z=720 (M+H)⁺.

Example 49.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate(racemate)

500 mg (1.29 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 495mg (1.89 mmol) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonateand 1.39 ml (1.39 mmol) of bis(trimethylsilyl)lithium amide (1M in THF)in 10 ml of THF were reacted according to General Method 7B.Purification by column chromatography (24 g silica cartridge, flow rate:35 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound.Yield: 386 mg (62% of theory)

LC/MS [Method 1]: R_(t)=1.18 min; MS (ESIpos): m/z=487 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.75-7.70 (m, 2H), 7.45(s, 1H), 6.52 (s, 1H), 5.14 (dd, 1H), 4.22-4.16 (m, 1H), 4.04-3.98 (m,1H), 3.63 (s, 3H), 2.59-2.51 (m, 2H), 1.40 (s, 9H).

Example 49.1B2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoicacid (racemate)

384 mg (789 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate(racemate) in 7.9 ml of dichloromethane and 2.28 ml (29.6 mmol) of TFAwere reacted according to General Method 6A. Yield: 330 mg (96% oftheory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=431 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.2 (s, 1H), 7.99 (d, 1H), 7.74-7.71(m, 2H), 7.50 (s, 1H), 6.51 (s, 1H), 5.18 (dd, 1H), 4.22-4.15 (m, 1H),4.02-3.95 (m, 1H), 3.63 (s, 3H), 2.62-2.51 (m, 2H).

Example 49.1C tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butano-yl}amino)benzoate(racemate)

330 mg (766 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoicacid (racemate), 148 mg (766 μmol) of tert-butyl 4-aminobenzoate, 109 mg(766 μmol) of Oxima and 120 μl (766 μmol) of DIC in 7.7 ml ofdimethylformamide were reacted according to General Method 5B. The crudeproduct was purified by flash chromatography (40 g cartridge, 40 ml/min,cyclohexane/ethyl acetate gradient). Yield: 329 mg (64% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=606 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.88 (d,2H), 7.77-7.71 (m, 4H), 7.51 (s, 1H), 6.56 (s, 1H), 5.81 (dd, 1H),4.20-4.14 (m, 1H), 4.03-3.95 (m, 1H), 3.69 (s, 3H), 2.68-2.60 (m, 2H),1.54 (s, 9H).

Example 50.1A 4-Bromo-2,5-dimethoxypyridine

A mixture of 2.25 g (12.05 mmol) of 2,5-dimethoxypyridin-4-ylboronicacid and 4.04 g (18.08 mmol, 1.5 eq.) copper(II) bromide in 48 ml ofmethanol/water (1:1) was irradiated in a microwave at 100° C. for 60min. After cooling, the precipitate was filtered, washed with water andthen stirred in 600 ml of methanol at 65° C. for 1 h and filtered. Theresidue was dissolved in dichloromethane, this solution was washed withdilute ammonia solution, dried (sodium sulphate), filtered, concentratedunder reduced pressure and dried. Yield: 1.71 g (65% of theory)

LC/MS [Method 3]: R_(t)=2.12 min; MS (ESIpos): m/z=218 (M+H)⁺.

Example 50.1B 4-Bromo-5-methoxypyridin-2(1H)-one

2.82 g (176 mmol, 20 eq.) of pyridinium hydrobromide were added to asolution of 1.94 g (8.81 mmol) of 4-bromo-2,5-dimethoxypyridine in 80 mlof dimethylformamide, the mixture was stirred at 100° C. for 3 h andconcentrated under reduced pressure. The residue was triturated with 50ml of water, filtered off, washed with water and dried under reducedpressure. The filtrate was extracted twice with dichloromethane/methanol(10:1). The combined organic phases were dried (sodium sulphate),filtered, concentrated under reduced pressure and dried. Yield: 771 mg(43% of theory) and 465 mg (purity 88%, 23% of theory)

LC/MS [Method 3]: R_(t)=1.38 min; MS (ESIpos): m/z=204 (M+H)⁺.

Example 50.1C 2-(4-Bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid(racemate)

Under argon, a suspension of 1.76 g (10.3 mmol, 2.0 eq.) of magnesiumdi-tert-butoxide, 1.24 g (5.15 mmol) of4-bromo-5-methoxypyridin-2(1H)-one and 607 mg (5.41 mmol, 1.05 eq.) ofpotassium tert-butoxide in 30 ml of tetrahydrofuran was stirred at RTfor 10 min. The reaction mixture was cooled in an ice bath, and 695 μl(7.72 mmol, 1.5 eq.) of 2-bromopropionic acid (racemate) were added. Thereaction mixture was then stirred initially at RT for another 2.5 h andthen further at 50° C. overnight, acidified with aqueous hydrochloricacid (6N) and diluted by addition of ethyl acetate/water. Theprecipitate formed was filtered off and dried under reduced pressure.Yield: 205 mg (14% of theory)

After phase separation of the filtrate, the aqueous phase was extractedwith ethyl acetate. The combined organic phases were dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was then once more reacted as described above with 1.05 g (6.18mmol) of magnesium di-tert-butylate, 376 mg (3.35 mmol) of potassiumtert-butylate and 371 μl (4.12 mmol) of 2-bromopropionic acid (racemate)in 30 ml of tetrahydrofuran and worked up analogously, with a furtherprecipitate being able to be isolated. Yield: 571 mg (39% of theory)

LC/MS [Method 1]: R_(t)=0.57 min; MS (ESIpos): m/z=276 (M+H)⁺.

Example 50.1D tert-Butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate)

571 mg (2.01 mmol) of2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and426 mg (2.21 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 562 mg (61% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=451 (M+H)⁺.

Example 50.1E tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

Under argon (in a flask dried by heating), 125 mg (0.28 mmol) oftert-butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate), 80 mg (0.33 mmol, 1.2 eq.) of5-chloro-2-trifluoromethoxyphenylboronic acid, 115 mg (0.83 mmol, 3.0eq.) of potassium carbonate and 23 mg (0.03 mmol, 0.1 eq.) of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxaneand stirred overnight in an oil bath already preheated to 110° C. Thereaction mixture was filtered through Celite and the residue was washedwith dioxane. The combined filtrates were concentrated under reducedpressure. The residue was triturated with water, filtered off, washedwith water and dried under reduced pressure. Yield: 155 mg (purity 83%,82% of theory)

LC/MS [Method 1]: R_(t)=1.34 min; MS (ESIpos): m/z=567 (M+H)⁺.

Example 50.2A tert-Butyl4-({2-[4-(2-bromo-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

Under argon (in a flask dried by heating), 113 mg (0.25 mmol) oftert-butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate), 70 mg (0.30 mmol, 1.2 eq.) of 2-bromo-5-chlorophenylboronicacid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxaneand stirred overnight in an oil bath already preheated to 110° C. Afurther 10 mg (0.01 mmol, 0.05 eq.) of[1,1-bis-(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct and 29 mg (0.12 mmol, 0.5 eq.) of2-bromo-5-chlorophenylboronic acid were added and the reaction mixturewas stirred at 110° C. for a further night and then filtered throughCelite. The residue was washed with dioxane. The combined filtrates wereconcentrated under reduced pressure. The residue was triturated withwater, filtered off, dried under reduced pressure and purified by flashchromatography (silica gel 50, cyclohexane/ethyl acetate gradient).Yield: 72 mg (purity 73%, 38% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=561 (M+H)⁺.

Example 50.3A tert-Butyl4-({2-[4-(5-chloro-2-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

Under argon (in a flask dried by heating), 92 mg (0.20 mmol) oftert-butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate), 41 mg (0.24 mmol, 1.2 eq.) of 5-chloro-2-methylphenylboronicacid, 84 mg (0.61 mmol, 3.0 eq.) of potassium carbonate and 16 mg (0.02mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxaneand stirred overnight in an oil bath already preheated to 110° C. Thereaction mixture was filtered through Celite and the residue was washedwith dioxane. The combined filtrates were concentrated under reducedpressure. The residue was triturated with water, filtered off, washedwith water and dried under reduced pressure. Yield: 105 mg (purity 91%,95% of theory)

LC/MS [Method 1]: R_(t)=1.26 min; MS (ESIpos): m/z=497 (M+H)⁺.

Example 50.4A tert-Butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

Under argon (in a flask dried by heating), 113 mg (0.25 mmol) oftert-butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate), 67 mg (0.30 mmol, 1.2 eq.) of5-chloro-2-trifluoromethylphenylboronic acid, 103 mg (0.74 mmol, 3.0eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxaneand stirred overnight in an oil bath already preheated to 110° C. Afurther 10 mg (0.01 mmol, 0.05 eq.) of[1,1-bis-(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct and 22 mg (0.10 mmol, 0.4 eq.) of5-chloro-2-trifluoromethylphenylboronic acid were added and the reactionmixture was stirred at 110° C. for a further 20 h and then filteredthrough Celite. The residue was washed with dioxane. The combinedfiltrates were concentrated under reduced pressure. The residue wastriturated with water, filtered off, washed with water and dried underreduced pressure. Yield: 145 mg (purity 84%, 89% of theory)

LC/MS [Method 1]: R_(t)=1.26 min; MS (ESIpos): m/z=551 (M+H)⁺.

Example 50.5A tert-Butyl4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

Under argon (in a flask dried by heating), 125 mg (0.27 mmol) oftert-butyl4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate(racemate), 92 mg (0.33 mmol, 1.2 eq.) of2-(5-chloro-2-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,114 mg (0.82 mmol, 3.0 eq.) of potassium carbonate and 22 mg (0.03 mmol,0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxaneand stirred overnight in an oil bath already preheated to 110° C. Thereaction mixture was filtered through Celite and the residue was washedwith dioxane. The combined filtrates were concentrated under reducedpressure. The residue was triturated with water, filtered off, washedwith water, dried under reduced pressure and purified by flashchromatography (silica gel-50, cyclohexane/ethyl acetate gradient).Yield: 114 mg (79% of theory)

LC/MS [Method 1]: R_(t)=1.30 min; MS (ESIpos): m/z=523 (M+H)⁺.

Example 51.1A 2-Bromo-4-chlorophenyl difluoromethyl ether

36 ml of aqueous potassium hydroxide solution (6M) were added to asolution of 3.5 g (16.9 mmol) of 2-bromo-4-chlorophenol in 36 ml ofacetonitrile, the mixture was cooled in an ice bath and 6.5 ml (26.9mmol, 1.6 eq.) of difluoromethyl trifluormethanesulphonate [Angew. Chem.Int. Ed. 2013, 52, 1-5; Journal of Fluorine Chemistry 2009, 130,667-670] were added dropwise with vigorous stirring. The reactionmixture was stirred for 5 min and diluted with 200 ml of water. Theaqueous phase was extracted twice with in each case 150 ml of diethylether. The combined organic phases were dried (sodium sulphate),filtered, concentrated under reduced pressure and dried. The aqueousphase was once more extracted with diethyl ether. The organic phase wasdried (sodium sulphate), filtered, concentrated under reduced pressureand dried. Yield of the two combined residues: 3.4 g (80% of theory)

LC/MS [Method 9]: R_(t)=3.51 min; MS (ESIpos): m/z=256 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.91 (d, 1H), 7.55 (dd, 1H), 7.37 (d,1H), 7.30 (t, 1H).

Example 51.1B4-[5-Chloro-2-(difluoromethoxy)phenyl]-2,5-dimethoxypyridine

417 mg (2.19 mmol, 1.2 eq.) of 2,5-dimethoxypyridin-4-ylboronic acid and494 mg (1.82 mmol) of 2-bromo-4-chlorophenyl difluoromethyl ether in thepresence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. The crude product was purified by flash chromatography(KP-SIL, petroleum ether/ethyl acetate 15-20%). Yield: 170 mg (purity90%, 27% of theory)

LC/MS [Method 1]: R_(t)=1.16 min; MS (ESIpos): m/z=316 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.96 (s, 1H), 7.57 (dd, 1H), 7.45 (d,1H), 7.30 (d, 1H), 7.11 (t, 1H), 6.74 (s, 1H), 3.83 (s, 3H), 3.75 (s,3H).

Example 51.1C4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one

170 mg (purity 90%, 0.49 mmol) of4-[5-chloro-2-(difluoromethoxy)phenyl]-2,5-dimethoxypyridine andpyridinium hydrobromide were reacted according to General Method 3A.Yield: 127 mg (87% of theory)

LC/MS [Method 1]: R_(t)=0.84 min; MS (ESIpos): m/z=302 (M+H)⁺.

Example 51.1D2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoicacid (racemate)

127 mg (0.42 mmol) of4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A at 90° C. Yield: 220 mg of crude product which wasreacted in the next step without further purification

Example 51.1E tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate)

220 mg of crude product of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoicacid (racemate) and 89 mg (0.46 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 48mg (21% of theory)

LC/MS [Method 1]: R_(t)=1.26 min; MS (ESIpos): m/z=549 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.70 (s, 1H), 7.87 (d, 2H), 7.73 (d,2H), 7.58 (dd, 1H), 7.48 (d, 1H), 7.35 (s, 1H), 7.30 (d, 1H), 7.16 (t,1H), 6.38 (s, 1H), 5.58 (q, 1H), 3.65 (s, 3H), 1.71 (d, 3H), 1.54 (s,9H).

Example 51.2A Ethyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridine-1(2H)-yl}butanoate(racemate)

Under argon and at RT, 105 mg (2.64 mmol, 1.3 eq.) of sodium hydride(60% in mineral oil) were added to a solution of 618 mg (2.03 mmol) of4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one in 25ml of tetrahydrofuran, the mixture was stirred at RT for 60 min 871 mg(2.64 mmol, 1.3 eq.) of ethyl2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) [J. Castells etal. Tetrahedron, 1994, 50, 13765-13774] were then added dropwise and themixture was stirred at RT for 1 h. A further 38 mg (0.96 mmol) of sodiumhydride (60% in mineral oil) were added, the reaction mixture wasstirred at RT for 5 min, a further 871 mg (2.64 mmol, 1.3 eq.) of ethyl2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate) were addeddropwise, and the reaction mixture was stirred at RT for 15 min and thenquenched with water. After phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The residuewas purified by flash chromatography (silica gel 50, cyclohexane/ethylacetate gradient). Yield: 415 mg (48% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=416 (M+H)⁺.

Example 51.2B2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridine-1(2H)-yl}butanoicacid (racemate)

415 mg (0.97 mmol) of ethyl2-{4-[5-Chloro-2-(difluormethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 348 mg (93% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=388 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.96 (br. s, 1H), 7.57 (dd, 1H),7.50 (d, 1H), 7.34-7.25 (m, 2H), 7.12 (t, 1H), 6.35 (s, 1H), 5.06 (dd,1H), 3.58 (s, 3H), 2.20-2.06 (m, 2H), 0.82 (t, 3H).

Example 51.2C tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]benzoate(racemate)

116 mg (0.30 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoicacid (racemate) and 64 mg (0.33 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 127mg (75% of theory)

LC/MS [Method 1]: R_(t)=1.32 min; MS (ESIpos): m/z=563 (M+H)⁺.

Example 52.1A 5-Ethoxy-4-iodo-2-methoxypyridine

At 0° C., 304 mg (1.95 mmol, 1.3 eq.) of iodoethane and 415 mg (3.0mmol, 2.0 eq.) of potassium carbonate were added to a solution of 405 mg(1.5 mmol) of 4-iodo-6-methoxypyridin-3-ol in 10 ml of acetone and themixture was stirred at 80° C. overnight and concentrated under reducedpressure. The residue was triturated with water, filtered and driedunder reduced pressure. Yield: 322 mg (purity 93%, 72% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=280 (M+H)⁺.

Example 52.1B 4-Chloro-2-(5-ethoxy-2-methoxypyridin-4-yl)benzonitrile

322 mg (purity 93%, 1.07 mmol) of 5-ethoxy-4-iodo-2-methoxypyridine and234 mg (1.29 mmol, 1.2 eq.) of 5-chloro-2-cyanophenylboronic acid in thepresence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. The crude product was purified by flash chromatography(silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 135 mg (41%of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=289 (M+H)⁺.

Example 52.1C4-Chloro-2-(5-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile

135 mg (0.44 mmol) of4-chloro-2-(5-ethoxy-2-methoxypyridin-4-yl)benzonitrile and pyridiniumhydrobromide were reacted according to General Method 3A. Yield: 134 mg(purity 76%, 83% of theory)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIpos): m/z=275 (M+H)⁺.

Example 52.1D2-[4-(5-Chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

134 mg (0.37 mmol) of4-chloro-2-(5-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and 1.5eq. of 2-bromopropanoic acid (racemate) were reacted according toGeneral Method 4A at 50° C. The crude product was purified bypreparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 89mg (purity 86%, 60% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=347 (M+H)⁺.

Example 52.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

89 mg (purity 86%, 0.22 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 47 mg (0.24 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 32mg (purity 89%, 25% of theory)

LC/MS [Method 3]: R_(t)=2.77 min; MS (ESIpos): m/z=522 (M+H)⁺.

Example 53.1A 5-(Difluoromethoxy)-4-iodo-2-methoxypyridine

4.8 ml of aqueous potassium hydroxide solution (6M) were added to asolution of 600 mg (purity 93%, 2.22 mmol) of4-iodo-6-methoxypyridin-3-ol in 4.8 ml of acetonitrile, the mixture wascooled in an ice bath and 863 μl (purity 75%, 3.56 mmol, 1.6 eq.) ofdifluoromethyl trifluoromethanesulphonate [Angew. Chem. Int. Ed. 2013,52, 1-5; Journal of Fluorine Chemistry 2009, 130, 667-670] were addedwith vigorous stirring. The reaction mixture was stirred for 2 min anddiluted with 33 ml of water. The aqueous phase was extracted twice within each case 40 ml of diethyl ether. The combined organic phases weredried (sodium sulphate), filtered, concentrated under reduced pressureand dried. The crude product was purified by flash chromatography(IR-50SI, petroleum ether/ethyl acetate 12-20%). Yield: 407 mg (purity90%, 55% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.1 (s, 1H), 7.45 (s, 1H), 7.16 (t,1H), 3.84 (s, 3H).

Example 53.1B4-Chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile

460 mg (purity 90%, 1.38 mmol) of5-(difluoromethoxy)-4-iodo-2-methoxypyridine and 299 mg (1.65 mmol, 1.2eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. The crude product was purified by flash chromatography(IR-50SI, petroleum ether/ethyl acetate 10-15%). Yield: 230 mg (purity80%, 43% of theory)

LC/MS [Method 1]: R_(t)=1.12 min; MS (ESIpos): m/z=311 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.26 (s, 1H), 8.06 (d, 1H), 7.82-7.74(m, 2H), 7.09 (s, 1H), 7.06 (t, 1H), 3.91 (s, 3H).

Example 53.1C4-Chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile

230 mg (purity 80%, 0.59 mmol) of4-chloro-2-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]benzonitrile andpyridinium hydrobromide were reacted according to General Method 3A. Thecrude product was purified by flash chromatography (IR-50SI,dichloromethane/methanol 3-25%). Yield: 167 mg (95% of theory)

LC/MS [Method 1]: R_(t)=0.79 min; MS (ESIpos): m/z=297 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.88 (br. s, 1H), 8.03 (d, 1H),7.80-7.65 (m, 3H), 6.87 (t, 1H), 6.56 (s, 1H).

Example 53.1D2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate)

163 mg (0.55 mmol) of4-chloro-2-[5-(difluoromethoxy)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile,2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassiumtert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) werereacted at 45° C. and worked up according to General Method 4A. Owing toincomplete conversion, the crude product was then once more reacted asdescribed above with 1.2 eq. of magnesium di-tert-butoxide, 0.65 eq. ofpotassium tert-butoxide and 0.8 eq. of 2-bromopropionic acid (racemate)in 3.5 ml of tetrahydrofuran and worked up analogously. Yield: 270 mg(purity 63%, 84% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=369 (M+H)⁺.

Example 53.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

270 mg (purity 63%, 0.46 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) and 98 mg (0.51 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 100mg (40% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=544 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.78 (s, 1H), 8.05 (d, 1H), 7.99 (s,1H), 7.88 (d, 2H), 7.82-7.69 (m, 4H), 6.89 (t, 1H), 6.65 (s, 1H), 5.56(q, 1H), 1.72 (d, 3H), 1.54 (s, 9H).

Example 54.1A 4-Iodo-2-methoxy-5-(2,2,2-trifluoroethoxy)pyridine

466 mg (3.4 mmol, 2.0 eq.) of potassium carbonate and 567 mg (2.5 mmol,1.5 eq.) of 2,2,2-trifluoroethyl trifluoromethanesulphonate were addedto a solution of 455 mg (purity 93%, 1.7 mmol) of4-iodo-6-methoxypyridin-3-ol in 10 ml of dimethylformamide and 0.4 ml ofacetonitrile, and the mixture was irradiated in a microwave at 150° C.for 30 min. A further 393 mg (1.7 mmol, 1.0 eq.) of 2,2,2-trifluoroethyltrifluoromethanesulphonate were added, and the reaction mixture was oncemore irradiated in the microwave at 150° C. for 30 min. After additionof water/ethyl acetate and phase separation, the aqueous phase wasextracted twice with ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered, concentrated under reduced pressure and dried.Yield: 500 mg (purity 94%, 94% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIpos): m/z=334 (M+H)⁺.

Example 54.1B4-Chloro-2-[2-methoxy-5-(2,2,2-trifluoroethoxy)pyridin-4-yl]benzonitrile

500 mg (purity 94%, 1.41 mmol) of4-iodo-2-methoxy-5-(2,2,2-trifluoroethoxy)pyridine and 282 mg (1.55mmol, 1.1 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of[1,1-bis(diphenylphosphino)ferrocene]palladium(II)chloride/dichloromethane monoadduct were reacted according to GeneralMethod 2A. The crude product was purified by flash chromatography(silica gel 50, cyclohexane/ethyl acetate gradient). Yield: 168 mg (33%of theory)

LC/MS [Method 1]: R_(t)=1.16 min; MS (ESIpos): m/z=343 (M+H)⁺.

Example 54.1C4-Chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile

168 mg (0.47 mmol) of4-chloro-2-[2-methoxy-5-(2,2,2-trifluoroethoxy)pyridin-4-yl]benzonitrileand pyridinium hydrobromide were reacted according to General Method 3A.Yield: 112 mg (purity 92%, 67% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=329 (M+H)⁺.

Example 54.1D2-[4-(5-Chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoicacid (racemate)

140 mg (purity 87%, 0.37 mmol) of4-chloro-2-[2-oxo-5-(2,2,2-trifluoroethoxy)-1,2-dihydropyridin-4-yl]benzonitrile,2.0 eq. of magnesium di-tert-butoxide, 1.05 eq. of potassiumtert-butoxide and 1.5 eq. of 2-bromopropanoic acid (racemate) werereacted according to General Method 4A at 50° C. and, after aqueouswork-up, used without purification for the next step. Yield: 214 mg(purity 73%, quant.)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=401 (M+H)⁺.

Example 54.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate)

214 mg (purity 73%, 0.39 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoicacid (racemate) and 83 mg (0.43 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 113mg (purity 70%, 35% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=576 (M+H)⁺.

Example 55.1A 2-Methoxybutyl trifluoromethanesulphonate (racemate)

1.0 g (9.6 mmol) of 2-methoxybutanol and 1.78 ml (10.6 mmol, 1.1 eq.) oftrifluoromethanesulphonic anhydride in the presence of 1.47 ml (10.6mmol, 1.1 eq.) of triethylamine were reacted according to General Method8A. The crude product was reacted in the next step without furtherpurification.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.51 (dd, 1H), 4.43 (dd, 1H), 3.44 (s,3H), 3.44-3.39 (m, 1H), 1.65-1.54 (m, 2H), 0.98 (t, 3H).

Example 55.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoate(mixture of racemic diastereomers)

1.00 g (2.67 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 2.94 ml (2.94 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 945 mg(4.00 mmol, 1.5 eq.) of 2-methoxybutyl trifluoromethanesulphonate(racemate) were reacted according to General Method 7B. Yield: 669 mg(54% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=461 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.98 (d, 1H), 7.75-7.70 (m, 2H),7.44/7.40 (2×s, 1H), 6.49/6.48 (2×s, 1H), 5.24-5.17 (m, 1H), 3.64 (2×s,3H), 3.19/3.16 (2×s, 3H), 2.81-2.74 (m, 1H), 2.45-2.28 (m, 1H),2.16-2.03 (m, 1H), 1.57-1.38 (m, 2H), 1.41 (2×s, 9H), 0.84/0.80 (2×t,3H).

Example 55.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoicacid (mixture of racemic diastereomers)

668 mg (1.45 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoate(mixture of racemic diastereomers) were hydrolysed with trifluoroaceticacid according to General Method 6A. Yield: 623 mg (purity 94%, quant.)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=405 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.0 (br. s, 1H), 7.98 (d, 1H),7.77-7.70 (m, 2H), 7.50/7.44 (2×s, 1H), 6.48/6.47 (2×s, 1H), 5.28-5.20(m, 1H), 3.64 (2×s, 3H), 3.16/3.15 (2×s, 3H), 2.78-2.71 (m, 1H),2.48-2.28 (m, 1H), 2.24-2.06 (m, 1H), 1.55-1.41 (m, 2H), 0.83/0.79 (2×t,3H).

Example 55.1D Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)-benzoate(mixture of racemic diastereomers)

620 mg (1.53 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoicacid (mixture of racemic diastereomers), 253 mg (1.53 mmol) of ethyl4-aminobenzoate, 218 mg (1.53 mmol) of Oxima and 239 μl (1.53 mmol) ofDIC in 15.3 ml of dimethylformamide were reacted according to GeneralMethod 5B. The crude product was purified by flash chromatography (120 gcartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 634 mg(70% of theory)

LC/MS [Method 2]: diastereomer 1: R_(t)=3.75 min; MS (ESIpos): m/z=552(M+H)⁺; diastereomer 2: R_(t)=3.81 min; MS (ESIpos): m/z=552 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (2×s, 1H), 8.01-7.98 (m, 1H),7.95-7.91 (m, 2H), 7.83-7.79 (m, 2H), 7.76-7.72 (m, 2H), 7.59/7.51 (2×s,1H), 6.54 (s, 1H), 5.87-5.80 (m, 1H), 4.31/4.29 (2×q, 2H), 3.69 (s, 3H),3.19/3.13 (2×s, 3H), 3.08-2.88 (2×m, 1H), 2.44-2.17 (m, 2H), 1.62-1.44(m, 2H), 1.31/1.28 (2×t, 3H), 0.86/0.85 (2×t, 3H).

Example 56.1A Benzyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate

3.18 g (23.0 mmol) of potassium carbonate were added to a solution of4.00 g (15.3 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile and2.92 ml (18.4 mmol) of benzyl bromoacetate in 53.3 ml ofdimethylformamide, and the mixture was then stirred at 100° C. for 45min. The reaction mixture was cooled to RT and the reaction was ended byadding 530 ml of water and 10.0 g (236 mmol) of lithium chloride. Themixture was extracted three times with 200 ml of ethyl acetate. Thecombined organic phases were dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The residue wasdissolved in 50 ml of dichloromethane, applied to diatomaceous earth andpurified by flash chromatography (120 g cartridge, 80 ml/min, ethylacetate/cyclohexane gradient). Yield: 3.90 g (61% of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=409 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (d, 1H), 7.75-7.72 (m, 2H), 7.61(s, 1H), 7.42-7.33 (m, 5H), 6.54 (s, 1H), 5.22 (s, 2H), 4.81 (s, 2H),3.62 (s, 3H).

Example 57.1A 2-{[tert-Butyl(diphenyl)silyl]oxy}ethanol

10.0 g (36.4 mmol) of chloro-tert-butyl(diphenyl)silane dissolved in 88ml of tetrahydrofuran were added dropwise over a period of 6 h to asolution of 10.1 ml (182 mmol) of 1,2-ethanediol and 2.97 g (43.7 mmol)of imidazole in 12 ml of tetrahydrofuran, and the mixture was thenstirred further at RT overnight. The solvent was removed under reducedpressure and the residue was purified by flash chromatography (340 gsilica cartridge, 100 ml/min, cyclohexane/ethyl acetate gradient).Yield: 8.34 g (76% of theory)

LC/MS [Method 1]: R_(t)=1.57 min; MS (ESIpos): m/z=323 (M+Na)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.66-7.62 (m, 4H), 7.49-7.40 (m, 6H),4.64 (t, 1H), 3.67-3.61 (m, 2H), 3.54-3.49 (m, 2H), 0.99 (s, 9H).

Example 57.1B 2-{[tert-Butyl(diphenyl)silyl]oxy}ethyltrifluoromethansulphonate

At −78° C., a solution of 1.50 g (4.99 mmol) of2-{[tert-butyl(diphenyl)silyl]oxy}ethanol and 765 μl (5.49 mmol) oftriethylamine in 5 ml of dichloromethane was added dropwise to 924 μl(5.49 mmol) of trifluoromethanesulphonic anhydride in 5 ml ofdichloromethane such that the internal temperature did not exceed −50°C. The mixture was stirred at −78° C. for another 15 min andspontaneously warmed to RT. The reaction mixture was diluted with 50 mlof methyl tert-butyl ether and washed three times with 25 ml of amixture of saturated aqueous sodium chloride solution and saturatedaqueous ammonium chloride solution (3:1), dried over magnesium sulphate,filtered and concentrated at 25° C. and a pressure of ≧100 mbar. Yield:2.08 g (71% of theory)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.66-7.62 (m, 4H), 7.52-7.44 (m, 6H),4.45-4.41 (m, 2H), 3.89-3.85 (m, 2H), 1.03 (s, 9H).

Example 57.1C Benzyl4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate(racemate)

1.00 g (2.45 mmol) of benzyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 2.69 ml (2.69 mmol, 1.1 eq.) ofbis(trimethylsilyl)lithium amide (1M in tetrahydrofuran) and 1.59 g(3.67 mmol, 1.5 eq.) of 2-{[tert-butyl(diphenyl)silyl]oxy}ethyltrifluoromethanesulphonate were reacted according to General Method 7B.Yield: 708 mg (40% of theory)

LC/MS [Method 1]: R_(t)=1.55 min; MS (ESIpos): m/z=691 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (d, 1H), 7.74 (dd, 1H),7.62-7.56 (m, 5H), 7.47-7.29 (m, 12H), 6.56 (s, 1H), 5.51 (dd, 1H), 5.19(s, 2H), 3.75-3.69 (m, 1H), 3.63-3.57 (m, 1H), 3.56 (s, 3H), 2.52-2.40(m, 2H), 0.97 (s, 9H).

Example 57.1D4-{[tert-Butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate)

605 mg (875 μmol) of benzyl4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate(racemate) were dissolved in 6 ml of tetrahydrofuran, and 2.2 ml (2.2mmol, 2.5 eq.) of aqueous sodium hydroxide solution (1.0M) were added.The mixture was stirred at RT for another 1 h and then neutralized withaqueous hydrochloric acid (1N). The phases were separated and theaqueous phase was extracted twice with 25 ml of ethyl acetate. Thecombined organic phases were dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The crude productwas used for the next step without further purification. Yield: 568 mg(93% of theory)

LC/MS [Method 1]: R_(t)=1.39 min; MS (ESIpos): m/z=601 (M+H)⁺.

Example 57.1E Ethyl4-[(4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl)amino]benzoate(racemate)

565 mg (940 μmol) of4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate), 155 mg (940 μmol) of ethyl 4-aminobenzoate, 134 mg (940μmol) of Oxima and 146 μl (940 μmol) of DIC in 19 ml ofdimethylformamide were reacted according to General Method 5B. The crudeproduct was purified by flash chromatography (120 g cartridge, 85ml/min, cyclohexane/ethyl acetate gradient). Yield: 268 mg (38% oftheory)

LC/MS [Method 1]: R_(t)=1.54 min; MS (ESIpos): m/z=748 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.94 (d,2H), 7.79 (d, 2H), 7.74 (dd, 1H), 7.63-7.57 (m, 5H), 7.48 (s, 1H),7.46-7.36 (m, 6H), 6.55 (s, 1H), 5.87 (dd, 1H), 4.29 (q, 2H), 3.72-3.67(m, 2H), 3.64 (s, 3H), 2.52-2.48 (m, 2H, under solvent resonance), 1.32(t, 3H), 0.94 (s, 9H).

Example 58.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)prop-2-enoate(isomer mixture)

38.4 mg (1.60 mmol, 2 eq., 60% in mineral oil) of sodium hydride and 457mg (4.00 mmol) of 3-ethyloxetane-3-carbaldehyde in 1 ml ofdimethylformamide were added in succession to a solution of 300 mg (800μmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 8ml of dimethylformamide. After 15 min at RT, the reaction was terminatedby addition of 10 ml of saturated aqueous ammonium chloride solution andthe reaction mixture was then extracted three times with 20 ml of ethylacetate. The combined organic phases were dried over magnesium sulphateand filtered, and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography (24 g cartridge, 35 ml/min,cyclohexane/ethyl acetate gradient). Yield: 320 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.06 min; MS (ESIpos): m/z=471 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00 (d, 1H), 7.79-7.71 (m, 2H), 7.27(s, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 4.63 (d, 1H), 4.48 (d, 1H), 4.22(d, 1H), 4.13 (d, 1H), 3.69/3.60 (2×s, 3H), 2.10-2.04/1.94-1.86 (2×q,2H), 1.44-1.40 (2×s, 9H), 0.99/0.95 (2×t, 3H).

Example 58.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoate(racemate)

At RT, 302 mg (641 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)prop-2-enoate(isomer mixture) were admixed with 20 ml of a “Hot Stryker's” reagentsolution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reactionmixture was stirred at RT for 1.5 h, and 20 ml of saturated aqueousammonium chloride solution were then added. After phase separation, theaqueous phase was extracted three times with 25 ml of ethyl acetate. Thecombined organic phases were dried over magnesium sulphate and filtered,and the solvent was removed under reduced pressure. The residue waspurified by flash chromatography (120 g silica cartridge, 85 ml/min,cyclohexane/ethyl acetate gradient). Yield: 275 mg (91% of theory)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIpos): m/z=473 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.98 (d, 1H), 7.75-7.71 (m, 2H), 7.51(s, 1H), 6.49 (s, 1H), 5.22-5.13 (m, 1H), 4.31 (d, 1H), 4.23 (d, 1H),4.04 (d, 1H), 3.93 (d, 1H), 3.65 (s, 3H), 2.65 (dd, 1H), 2.39 (dd, 1H),1.83-1.72 (m, 2H), 1.41 (s, 9H), 0.83 (t, 3H).

Example 58.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoicacid (racemate)

275 mg (599 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoate(racemate) and 3 ml of aqueous lithium hydroxide solution (1N) werereacted according to General Method 6B, giving the title compound.Yield: 193 mg (76% of theory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIpos): m/z=417 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (br. s, 1H), 7.99 (d, 1H),7.77-7.71 (m, 2H), 7.56 (s, 1H), 6.49 (s, 1H), 5.25-5.13 (m, 1H), 4.30(d, 1H), 4.22 (d, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 3.65 (s, 3H), 2.69(dd, 1H), 2.42 (dd, 1H), 1.84-1.73 (m, 2H), 0.82 (t, 3H).

Example 59.1A 1,1,2,2,2-Pentadeuteroethyl trifluoromethanesulphonate

1.0 g (19.57 mmol) of 1,1,2,2,2-pentadeuteroethanol and 3.48 ml (20.55mmol, 1.05 eq.) of trifluoromethanesulphonic anhydride in the presenceof 2.51 ml (21.53 mmol, 1.1 eq.) of 2,6-dimethylpyridine were reactedaccording to General Method 8A. The crude product was reacted in thenext step without further purification.

Example 59.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoate(racemate)

250 mg (0.67 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 0.80 ml (0.80 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 183 mg (1.00 mmol, 1.5eq.) of 1,1,2,2,2-pentadeuteroethyl trifluoromethanesulphonate werereacted according to General Method 7B. Yield: 206 mg (purity 94%, 71%of theory)

LC/MS [Method 8]: R_(t)=1.37 min; MS (ESIpos): m/z=352(M+H—COO-tert-butyl)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.76-7.69 (m, 2H), 7.36(s, 1H), 6.50 (s, 1H), 5.01 (s, 1H), 3.63 (s, 3H), 1.40 (s, 9H).

Example 59.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoicacid (racemate)

206 mg (purity 94%, 0.48 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 208 mg (purity 71%, 88% of theory)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIpos): m/z=352 (M+H)⁺.

Example 59.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoyl}amino)benzoate(racemate)

208 mg (purity 71%, 0.42 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoicacid (racemate) and 89 mg (0.46 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 79mg (purity 91%, 33% of theory)

LC/MS [Method 1]: R_(t)=1.21 min; MS (ESIpos): m/z=527 (M+H)⁺.

Example 60.1A [1-(Trifluoromethyl)cyclopropyl]methanol

At 0° C., 26.7 ml (26.7 mmol) of diisobutylaluminum hydride (1M indichloromethane) were slowly added dropwise to a solution of 1.89 g(10.7 mmol) of methyl 1-(trifluoromethyl)cyclopropanecarboxylate in 10ml of dichloromethane. The mixture was then stirred at 0° C. for another2 h and the reaction was subsequently terminated by addition of 10 ml ofmethanol. The reaction mixture was diluted with 30 ml of aqueous 20%strength sodium potassium tartrate solution and 30 ml of aqueous buffersolution (pH 7) and stirred vigorously at room temperature overnight.The phases were separated and the aqueous phase was extracted threetimes with dichloromethane. The combined organic phases were dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The crude product corresponded to the title compound.Yield: 0.96 g (64% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.74 (d, 2H), 1.65 (t, 1H), 1.06-1.02(m, 2H), 0.81-0.76 (m, 2H).

Example 60.1B [1-(Trifluoromethyl)cyclopropyl]methyltrifluoromethanesulphonate

At −78° C., a solution of 428 mg (3.06 mmol) of[1-(trifluoromethyl)cyclopropyl]methanol and 468 μl (3.36 mmol) oftriethylamine in 1.5 ml of dichloromethane was added dropwise to 569 μl(3.36 mmol) of trifluoromethanesulphonic anhydride in 1.5 ml ofdichloromethane such that the internal temperature did not exceed −50°C. The mixture was stirred at −78° C. for another 30 min andspontaneously warmed to RT. The reaction mixture was diluted with 25 mlof methyl tert-butyl ether, washed three times with 20 ml of a mixtureof saturated aqueous sodium chloride solution/1N hydrochloric acid(3:1), dried over magnesium sulphate, filtered and concentrated at 25°C. and a pressure of ≧100 mbar. The crude product was used for the nextstep without further purification. Yield: 701 mg (84% of theory)

Example 60.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoate(racemate)

500 mg (1.33 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 701mg (2.58 mmol) of [1-(trifluoromethyl)cyclopropyl]methyltrifluoromethanesulphonate and 1.73 ml (1.73 mmol) ofbis(trimethylsilyl)lithium amide (1M in THF) in 13 ml of THF werereacted according to General Method 7B. The crude product was purifiedby column chromatography (ethyl acetate/cyclohexane gradient, 40 gsilica cartridge, flow rate 40 ml/min), giving the title compound.Yield: 295 mg (45% of theory)

LC/MS [Method 1]: R_(t)=1.20 min; MS (ESIpos): m/z=497 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.75-7.71 (m, 2H), 7.42(s, 1H), 6.50 (s, 1H), 5.19-5.11 (m, 1H), 3.63 (s, 3H), 2.68 (dd, 1H),2.33 (dd, 1H), 1.40 (s, 9H), 0.95-0.74 (m, 3H), 0.56-0.49 (m, 1H).

Example 60.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoicacid (racemate)

295 mg (594 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoate(racemate) in 6 ml of dichloromethane and 915 μl (11.9 mmol) of TFA werereacted according to General Method 6A. Yield: 258 mg (purity 92%, 91%of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIneg): m/z=439 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.2 (br. s, 1H), 7.99 (d, 1H),7.76-7.71 (m, 2H), 7.46 (s, 1H), 6.49 (s, 1H), 5.23-5.14 (m, 1H), 3.63(s, 3H), 2.71 (dd, 1H), 2.37 (dd, 1H), 0.92-0.81 (m, 2H), 0.78-0.71 (m,1H), 0.54-0.46 (m, 1H).

Example 60.1E tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoate(racemate)

188 mg (426 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoicacid (racemate), 82.4 mg (426 μmol) of tert-butyl 4-aminobenzoate, 6.1mg (43 μmol) of Oxima and 66 μl (0.43 mmol) of DIC in 4 ml ofdimethylformamide were reacted according to General Method 5B. Followingpreparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobilephase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90%acetonitrile)], the title compound was obtained. Yield: 157 mg (59% oftheory)

LC/MS [Method 1]: R_(t)=1.35 min; MS (ESIpos): m/z=616 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 7.99 (d, 1H), 7.88 (d,2H), 7.78-7.71 (m, 4H), 7.53 (s, 1H), 6.55 (s, 1H), 5.86-5.80 (m, 1H),3.67 (s, 3H), 2.60-2.47 (m, 2H), 1.54 (s, 9H), 0.97-0.80 (m, 4H).

Example 61.1A [1-(Trifluoromethyl)cyclobutyl]methyltrifluoromethanesulphonate

330 mg (2.03 mmol) of [1-(trifluoromethyl)cyclobutyl]methanol and 0.38ml (2.24 mmol, 1.1 eq.) of trifluoromethanesulphonic anhydride in thepresence of 312 μl (2.24 mmol, 1.1 eq.) of triethylamine were reactedaccording to General Method 8A. The crude product was reacted in thenext step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.56 (s, 2H), 2.28-2.19 (m, 2H),2.11-1.89 (m, 4H).

Example 61.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoate(racemate)

383 mg (1.02 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.23 ml (1.23 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 780 mg (purity 60%,1.64 mmol, 1.6 eq.) of [1-(trifluoromethyl)cyclobutyl]methyltrifluoromethanesulphonate were reacted according to General Method 7B.Yield: 119 mg (purity 91%, 21% of theory)

LC/MS [Method 8]: R_(t)=1.54 min; MS (ESIpos): m/z=455(M+H—COO-tert-butyl)⁺.

Example 61.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoicacid (racemate)

119 mg (purity 91%, 0.21 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 91 mg (purity 69%, 65% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=455 (M+H)⁺.

Example 61.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)-cyclobutyl]propanoyl}amino)benzoate(racemate)

90 mg (purity 69%, 0.14 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoicacid (racemate) and 29 mg (0.15 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 58mg (67% of theory)

LC/MS [Method 8]: R_(t)=1.65 min; MS (ESIneg): m/z=628 (M−H)⁻.

Example 62.1A (3,3-Difluorocyclobutyl)methyl trifluoromethanesulphonate

500 mg (4.09 mmol) of (3,3-difluorocyclobutyl)methanol and 0.76 ml (4.50mmol, 1.1 eq.) of trifluoromethanesulphonic anhydride in the presence of628 μl (4.50 mmol, 1.1 eq.) of triethylamine were reacted according toGeneral Method 8A. The crude product was reacted in the next stepwithout further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.33 (d, 2H), 2.76-2.61 (m, 2H),2.60-2.50 (m, 1H), 2.50-2.37 (m, 2H).

Example 62.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoate(racemate)

600 mg (1.60 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.92 ml (1.92 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 1162 mg (purity 70%,3.20 mmol, 2.0 eq.) of (3,3-difluorocyclobutyl)methyltrifluoromethanesulphonate were reacted according to General Method 7B.Yield: 417 mg (52% of theory)

LC/MS [Method 8]: R_(t)=1.44 min; MS (ESIpos): m/z=423(M+H—COO-tert-butyl)⁺.

Example 62.1C2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoicacid (racemate)

184 mg (0.37 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 200 mg (purity 88%, quant.)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=423 (M+H)⁺.

Example 62.1D tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoyl}amino)benzoate(racemate)

200 mg (purity 88%, 0.42 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpropanoicacid (racemate) and 89 mg (0.46 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 175mg (70% of theory)

LC/MS [Method 1]: R_(t)=1.26 min; MS (ESIpos): m/z=598 (M+H)⁺.

Example 63.1A 3-Methyloxetane-3-carbaldehyde

6.75 g (31.3 mmol) of pyridinium chlorochromate were initially chargedin 100 ml of dichloromethane, and a solution of 2.00 g (19.6 mmol) of(3-methyloxetan-3-yl)methanol in 20 ml of dichloromethane was added atroom temperature. 7 g of Celite® were then added, and the mixture wasstirred at room temperature for another 4 h. The mixture was filteredoff with suction through silica gel and the solvent was removed underreduced pressure at room temperature. The crude product was used for thenext step without further purification. Yield: 1.55 g (79% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=9.95 (s, 1H), 4.89 (d, 2H), 4.51 (d,2H), 1.48 (s, 3H).

Example 63.1B tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)prop-2-enoate(isomer mixture)

64.0 mg (1.60 mmol, 60% in mineral oil) of sodium hydride and 200 mg(2.00 mmol) of 3-methyloxetane-3-carbaldehyde in 1 ml ofdimethylformamide were added in succession to a solution of 300 mg (800μmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 9ml of dimethylformamide. After 15 min at room temperature, the reactionwas terminated by addition of saturated aqueous ammonium chloridesolution and the reaction mixture was then extracted three times with 20ml of ethyl acetate. The combined organic phases were dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The residue was purified by flash chromatography (24 gsilica cartridge, flow rate 35 ml/min, cyclohexane/ethyl acetategradient). Yield: 356 mg (96% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=457 (M+H)⁺.

Example 63.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoate(racemate)

At room temperature, 350 mg (766 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)prop-2-enoate(isomer mixture) were admixed with 20 ml of a “Hot Stryker's” reagentsolution [B. A. Baker et al. Org. Lett. 2008, 10, 289-292]. The reactionmixture was stirred at room temperature for 1 h, and saturated aqueousammonium chloride solution was then added. After phase separation, theaqueous phase was extracted three times with ethyl acetate. The combinedorganic phases were dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The residue was purified byflash chromatography (40 g silica cartridge, flow rate 40 ml/min,cyclohexane/ethyl acetate gradient). Yield: 345 mg (97% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=459 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.98 (d, 1H), 7.75-7.70 (m, 2H), 7.47(s, 1H), 6.50 (s, 1H), 5.25-5.18 (m, 1H), 4.38 (d, 1H), 4.16 (d, 1H),4.07 (d, 1H), 3.92 (d, 1H), 3.65 (s, 3H), 2.67 (dd, 1H), 2.31 (dd, 1H),1.41 (s, 9H), 1.35 (s, 3H).

Example 63.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoicacid (racemate)

340 mg (741 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoate(racemate) were dissolved in 5 ml of tetrahydrofuran, 2.5 ml of ethanoland 2.5 ml of water, and 3.7 ml (3.7 mmol, 5 eq.) of aqueous lithiumhydroxide solution (1M) were added. The mixture was stirred at roomtemperature for another 7 h and then diluted with 20 ml of saturatedaqueous ammonium chloride solution and 30 ml of ethyl acetate andadjusted to pH 4-5 using aqueous hydrochloric acid (1N). The phases wereseparated and the aqueous phase was extracted three times with 10 ml ofethyl acetate. The combined organic phases were dried over magnesiumsulphate and filtered, and the solvent was removed under reducedpressure. The crude product was used for the next step without furtherpurification. Yield: 275 mg (purity 95%, 88% of theory)

LC/MS [Method 1]: R_(t)=0.78 min; MS (ESIneg): m/z=401 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.2 (br. s, 1H), 7.99 (d, 1H),7.77-7.71 (m, 2H), 7.53 (s, 1H), 6.49 (s, 1H), 5.31-5.22 (m, 1H), 4.37(d, 1H), 4.16 (d, 1H), 4.05 (d, 1H), 3.90 (d, 1H), 3.65 (s, 3H), 2.71(dd, 1H), 2.33 (dd, 1H), 1.35 (s, 3H).

Example 63.1E Allyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoyl}amino)benzoate(racemate)

115 mg (285 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoicacid (racemate), 51 mg (285 μmol) of allyl 4-aminobenzoate, 40.6 mg (285μmol) of Oxima and 45 μl (0.29 mmol) of DIC in 2 ml of dimethylformamidewere reacted according to General Method 5B. Preparative HPLC(acetonitrile/water gradient) gave the title compound. Yield: 25 mg (16%of theory)

LC/MS [Method 1]: R_(t)=1.06 min; MS (ESIpos): m/z=562 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.01-7.96 (m, 3H), 7.80(d, 2H), 7.74-7.71 (m, 2H), 7.65 (s, 1H), 6.53 (s, 1H), 6.09-5.99 (m,1H), 5.87 (dd, 1H), 5.43-5.37 (m, 1H), 5.30-5.25 (m, 1H), 4.80-4.77 (m,2H), 4.46 (d, 1H), 4.29 (d, 1H), 4.11 (d, 1H), 3.95 (d, 1H), 3.72 (s,3H), 2.74-2.65 (m, 1H), 2.40-2.33 (m, 1H), 1.38 (s, 3H).

Example 64.1A Methyl 4-methyltetrahydro-2H-pyran-4-carboxylate

At −78° C., 22.1 ml of n-butyllithium (35.4 mmol, 1.6M in hexane) wereslowly added dropwise to a solution of 4.91 ml (35.0 mmol) ofdiisopropylamine in 45 ml of tetrahydrofuran, and the mixture wasstirred at −78° C. for another 10 min and at 0° C. for another 25 min.Subsequently, at −78° C., a solution of 5.00 g (34.7 mmol) of methyltetrahydro-2H-pyran-4-carboxylate in 45 ml of tetrahydrofuran was added,and the mixture was stirred at −78° C. for another 15 min and at 0° C.for another 30 min. At −78° C., 2.16 ml (34.7 mmol) of methyl iodidewere added dropwise, and the reaction mixture was slowly warmed to −25°C. and then to room temperature overnight. The reaction was terminatedby addition of 80 ml of 0.1N hydrochloric acid, and the phases wereseparated. The aqueous phase was extracted twice with ethyl acetate, thecombined organic phases were dried over magnesium sulphate and filteredand the solvent was removed under reduced pressure. The resultingsuspension was triturated with 20 ml of methyl tert-butyl ether, theprecipitate was filtered off with suction and the mother liquor wasconcentrated under reduced pressure, giving the title compound. Yield:5.88 g (purity 95%, quant.)

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.70-3.64 (m, 2H), 3.64 (s, 3H),3.37-3.30 (m, 2H), 1.94-1.88 (m, 2H), 1.45-1.37 (m, 2H), 1.16 (s, 3H).

Example 64.1B (4-Methyltetrahydro-2H-pyran-4-yl)methanol

At −78° C., 73.3 ml (73.3 mmol, 1.0M in toluene) of diisobutylaluminiumhydride were added dropwise to a solution of 5.80 g (36.7 mmol) ofmethyl 4-methyltetrahydro-2H-pyran-4-carboxylate in 220 ml of toluenesuch that the internal temperature did not exceed −70° C. The mixturewas subsequently stirred at −78° C. for another 90 min and then furtherat room temperature overnight. The reaction was terminated by additionof 40 ml of methanol and 300 ml of 1N hydrochloric acid. The phases wereseparated and the aqueous phase was extracted three times with 150 ml ofethyl acetate. The combined organic phases were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulphate andfiltered, and the solvent was removed under reduced pressure. The crudeproduct corresponded to the title compound. Yield: 2.14 g (45% oftheory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.78-3.73 (m, 2H), 3.66-3.60 (m, 2H),3.41 (s, 2H), 1.62-1.54 (m, 2H), 1.43 (br. s, 1H), 1.32-1.26 (m, 2H),1.04 (s, 3H).

Example 64.1C (4-Methyltetrahydro-2H-pyran-4-yl)methyltrifluoromethanesulphonate

At −78° C., a solution of 1.00 g (7.68 mmol) of(4-methyltetrahydro-2H-pyran-4-yl)methanol and 1.18 ml (8.45 mmol) oftriethylamine in 5 ml of dichloromethane was added dropwise to 1.42 ml(8.45 mmol) of trifluoromethanesulphonic anhydride in 5 ml ofdichloromethane such that the internal temperature did not exceed −50°C. The mixture was stirred at −78° C. for another 15 min andspontaneously warmed to RT. The reaction mixture was diluted with 50 mlof methyl tert-butyl ether, washed three times with 25 ml of a mixtureof saturated aqueous sodium chloride solution/1N hydrochloric acid(3:1), dried over magnesium sulphate, filtered and concentrated at 25°C. and a pressure of ≧100 mbar. Yield: 2.0 g (99% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.26 (s, 2H), 3.80-3.74 (m, 2H),3.67-3.60 (m, 2H), 1.66-1.58 (m, 2H), 1.42-1.36 (m, 2H), 1.16 (s, 3H).

Example 64.1D tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoate(racemate)

1.91 g (5.08 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate,2.00 g (7.63 mmol) of (4-methyltetrahydro-2H-pyran-4-yl)methyltrifluoromethanesulphonate and 6.61 ml (6.61 mmol) ofbis(trimethylsilyl)lithium amide (1M in THF) in 10 ml of THF werereacted according to General Method 7B. Purification by preparative HPLC(acetonitrile/water gradient) gave the title compound. Yield: 212 mg (8%of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=487 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=8.00-7.96 (m, 1H), 7.74-7.70 (m, 2H),7.50 (s, 1H), 6.48 (s, 1H), 5.48-5.41 (m, 1H), 3.66 (s, 3H), 3.55-3.42(m, 4H), 2.30-2.22 (m, 1H), 2.15-2.09 (m, 1H), 1.49-1.10 (m, 4H), 1.41(s, 9H), 0.95 (s, 3H).

Example 64.1E2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoicacid (racemate)

210 mg (431 μmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoate(racemate) in 4.3 ml of dichloromethane and 598 μl (7.76 mmol) of TFAwere reacted according to General Method 6A. Yield: 210 mg (purity 83%,94% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIneg): m/z=429 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.2 (br. s, 1H), 7.98 (d, 1H),7.75-7.70 (m, 2H), 7.55 (s, 1H), 6.48 (s, 1H), 5.58-5.43 (m, 1H), 3.65(s, 3H), 3.55-3.38 (m, 4H), 2.37-2.31 (m, 1H), 2.18-2.12 (m, 1H),1.48-1.41 (m, 1H), 1.35-1.28 (m, 1H), 1.27-1.19 (m, 1H), 1.13-1.06 (m,1H), 0.96 (s, 3H).

Example 64.1F Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate(racemate)

206 mg (478 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoicacid (racemate), 79 mg (0.48 mmol) of ethyl 4-aminobenzoate, 6.8 mg (48μmol) of Oxima and 74 μl (0.48 mmol) of DIC in 4.8 ml ofdimethylformamide were reacted according to General Method 5B.Preparative HPLC (acetonitrile/water gradient) gave the title compound.Yield: 70 mg (purity 95%, 24% of theory)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=578 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 7.98 (d, 1H), 7.94 (d,2H), 7.80 (d, 2H), 7.75-7.71 (m, 2H), 7.66 (s, 1H), 6.52 (s, 1H), 6.05(dd, 1H), 4.29 (q, 2H), 3.71 (s, 3H), 3.65-3.39 (m, 4H), 2.34-2.27 (m,1H), 2.07-2.00 (m, 1H), 1.57-1.48 (m, 1H), 1.40-1.25 (m, 2H), 1.31 (t,3H), 1.16-1.09 (m, 1H), 1.03 (s, 3H).

Example 65.1A Methyl 4-methoxycyclohexanecarboxylate (cis/trans isomermixture)

1.8 ml of concentrated sulphuric acid were added to a solution of 4.00 g(25.3 mmol) of 4-methoxycyclohexanecarboxylic acid in 32 ml of methanol,and the resulting reaction solution was heated under reflux overnight.The mixture was cooled to room temperature and the pH was adjusted to7-8 using saturated aqueous sodium bicarbonate solution. The mixture wasthen extracted three times with 70 ml of ethyl acetate. The combinedorganic phases were dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude productcorresponded to the title compound. Yield: 4.30 g (99% of theory)

GC/MS [Method 9]: Rt=3.65 min; MS: m/z=172 (M)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.58 (s, 3H), 3.33-3.29/3.11-3.04(2×m, 1H), 3.22/3.19 (2×s, 3H), 2.42-2.35/2.31-2.23 (2×m, 1H),2.00-1.93/1.92-1.85 (2×m, 1H), 1.73-1.61 (m, 3H), 1.58-1.43 (m, 3H),1.41-1.30/1.19-1.08 (2×m, 1H).

Example 65.1B (4-Methoxycyclohexyl)methanol (cis/trans isomer mixture)

13.7 ml (27.5 mmol) of lithium aluminium hydride solution (2M in THF)was diluted with 82 ml of methyl tert-butyl ether, and a solution of4.30 g (25.0 mmol) of methyl 4-methoxycyclohexanecarboxylate (cis/transisomer mixture) in 82 ml of methyl tert-butyl ether was then addeddropwise. The reaction solution was stirred at 40° C. for another 6 hand the reaction was then terminated by addition of 10 ml of water and10 ml of aqueous 10% strength potassium hydroxide solution. The organicphase was decanted, dried over sodium sulphate and filtered, and thesolvent was removed under reduced pressure. Yield: 3.24 g (90% oftheory)

GC/MS [Method 9]: Rt=3.36/3.47 min; MS: m/z=144 (M)⁺

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.48/3.46 (2×d, 2H),3.45-3.42/3.13-3.06 (2×m, 1H), 3.35/3.30 (2×s, 3H), 2.13-1.82 (m, 2H),1.65 (br. s, 1H), 1.59-1.29 (m, 6H), 1.24-1.15/1.03-0.95 (2×m, 1H).

Example 65.1C (4-Methoxycyclohexyl)methyl trifluoromethanesulphonate(cis/trans isomer mixture)

4.30 g (29.8 mmol) of (4-methoxycyclohexyl)methanol (cis/trans isomermixture) in 158 ml of dichloromethane and 5.21 ml (44.7 mmol) oflutidine and 7.57 ml (44.7 mmol) of trifluoromethanesulphonic anhydridewere reacted according to General Method 8A. Yield: 6.00 g (73% oftheory). The crude product was used for the next step without furtherpurification.

Example 65.1D tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methoxycyclohexyl)propanoate(racemic cis/trans isomer mixture)

5.40 g (14.4 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate,5.97 g (21.6 mmol) of (4-methoxycyclohexyl)methyltrifluoromethanesulphonate (cis/trans isomer mixture) and 15.8 ml (15.8mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 114 ml of THFwere reacted according to General Method 7B. Yield: 10.8 g (purity 51%)of crude product

LC/MS [Method 1]: R_(t)=1.20/1.23 min; MS (ESIpos): m/z=501 (M+H)⁺.

Example 65.1E tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoate(racemate)

The crude product from Example 65.1D was purified by columnchromatography (ethyl acetate/cyclohexane gradient, 340 g silicacartridge, flow rate 100 ml/min), giving the title compound. Yield: 2.1g (29% of theory)

LC/MS [Method 1]: R_(t)=1.18 min; MS (ESIpos): m/z=501 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.76-7.71 (m, 2H), 7.38(s, 1H), 6.50 (s, 1H), 5.31-5.26 (m, 1H), 3.64 (s, 3H), 3.18 (s, 3H),2.16-2.07 (m, 1H), 1.97-1.90 (m, 1H), 1.79-1.70 (m, 2H), 1.57-1.51 (m,1H), 1.44-1.13 (m, 6H), 1.40 (s, 9H).

Example 65.2E tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoate(racemate)

The crude product from Example 65.1D was purified by columnchromatography (ethyl acetate/cyclohexane gradient, 340 g silicacartridge, flow rate 100 ml/min), giving the title compound. Yield: 1.7g (purity 87%, 21% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=501 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.77-7.71 (m, 2H), 7.39(s, 1H), 6.50 (s, 1H), 5.28-5.22 (m, 1H), 3.64 (s, 3H), 3.20 (s, 3H),3.07-2.98 (m, 1H), 2.17-2.08 (m, 1H), 1.98-1.83 (m, 4H), 1.68-1.61 (m,1H), 1.40 (s, 9H), 1.07-0.89 (m, 5H).

Example 65.1F2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoicacid (racemate)

2.10 g (4.19 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoate(racemate) in 6 ml of dichloromethane and 6.23 ml (83.8 mmol) of TFAwere reacted according to General Method 6A. Yield: 2.10 g (quant.)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIneg): m/z=443 (M−H)⁻.

Example 65.2F2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoicacid (racemate)

1.70 g (purity 87%, 3.39 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoate(racemate) in 6 ml of dichloromethane and 5.04 ml (67.9 mmol) of TFAwere reacted according to General Method 6A. Yield: 1.70 g (quant.)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIneg): m/z=443 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.0 (br. s, 1H), 7.98 (d, 1H),7.76-7.70 (m, 2H), 7.43 (s, 1H), 6.49 (s, 1H), 5.34-5.26 (m, 1H), 3.64(s, 3H), 3.19 (s, 3H), 3.06-2.97 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.81(m, 4H), 1.64-1.57 (m, 1H), 1.06-0.86 (m, 5H).

Example 65.1G Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoate(racemate)

2.10 g (purity 74%, 4.72 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoicacid (racemate), 780 mg (4.72 mmol) of ethyl 4-aminobenzoate, 671 mg(4.72 mmol) of Oxima and 735 μl (4.72 mmol) of DIC in 47 ml ofdimethylformamide were reacted according to General Method 5B. Aftercomplete conversion, the reaction solution was diluted with 263 ml of10% strength lithium chloride solution and 210 ml of ethyl acetate andthe phases were separated. The aqueous phase was extracted twice with210 ml of ethyl acetate. The combined organic phases were dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The crude product was purified by columnchromatography (ethyl acetate/cyclohexane gradient, 100 g silicacartridge, flow rate 50 ml/min), giving the title compound. Yield: 2.1 g(75% of theory)

LC/MS [Method 1]: R_(t)=1.26 min; MS (ESIpos): m/z=592 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 7.99 (d, 1H), 7.94 (d,2H), 7.78 (d, 2H), 7.76-7.71 (m, 2H), 7.49 (s, 1H), 6.53 (s, 1H),5.87-5.81 (m, 1H), 4.29 (q, 2H), 3.69 (s, 3H), 3.19 (s, 3H), 2.25-2.14(m, 1H), 2.02-1.92 (m, 1H), 1.82-1.70 (m, 2H), 1.52-1.12 (m, 7H), 1.31(t, 3H).

Example 65.2G Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoate(racemate)

1.70 g (purity 82%, 3.82 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoicacid (racemate), 631 mg (3.82 mmol) of ethyl 4-aminobenzoate, 543 mg(3.82 mmol) of Oxima and 595 μl (3.82 mmol) of DIC in 38 ml ofdimethylformamide were reacted according to General Method 5B. Aftercomplete conversion, the reaction solution was diluted with 213 ml of10% strength lithium chloride solution and 170 ml of ethyl acetate andthe phases were separated. The aqueous phase was extracted twice with170 ml of ethyl acetate. The combined organic phases were dried overmagnesium sulphate and filtered, and the solvent was removed underreduced pressure. The crude product was purified by columnchromatography (ethyl acetate/cyclohexane gradient, 100 g silicacartridge, flow rate 50 ml/min), giving the title compound. Yield: 1.1 g(purity 78%, 49% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=592 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 7.99 (d, 1H), 7.94 (d,2H), 7.80-7.71 (m, 4H), 7.49 (s, 1H), 6.54 (s, 1H), 5.87-5.81 (m, 1H),4.29 (q, 2H), 3.69 (s, 3H), 3.20 (s, 3H), 3.08-2.98 (m, 1H), 2.24-2.15(m, 1H), 2.00-1.88 (m, 3H), 1.83-1.72 (m, 2H), 1.31 (t, 3H), 1.12-0.89(m, 5H).

Example 66.1A tert-Butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate)

114 mg (purity 94%, 0.35 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 103 mg (0.39 mmol, 1.1 eq.) of tert-butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate werereacted according to General Method 5A. The crude product was purifiedby preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield:101 mg (45% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=632 (M+H)⁺.

Example 67.1A Ethyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoate(racemate)

3.50 g (13.4 mmol) of4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in thepresence of 1.5 eq. of sodium hydride and 5.60 g (20.1 mmol, 1.5 eq.) ofethyl 3-methyl-2-{[(trifluoromethyl)sulphonyl]oxy}butanoate (racemate)were reacted at RT according to General Method 4E. The crude product waspurified by flash chromatography (silica gel 50, cyclohexane/ethylacetate mixtures). Yield: 3.70 g (66% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=389 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.76 (d, 1H), 7.73 (dd,1H), 7.43 (s, 1H), 6.51 (s, 1H), 5.00-4.95 (m, 1H), 4.21-4.11 (m, 2H),3.65 (s, 3H), 2.65-2.56 (m, 1H), 1.19 (t, 3H), 1.11 (d, 3H), 0.76 (d,3H).

Example 67.1B2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate)

3.70 g (9.52 mmol) of ethyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 6B. Yield: 2.80 g (82% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=361 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.1 (br. s, 1H), 7.99 (d, 1H), 7.76(d, 1H), 7.73 (dd, 1H), 7.41 (s, 1H), 6.51 (s, 1H), 4.94 (d, 1H), 3.64(s, 3H), 2.62-2.56 (m, 1H), 1.12 (d, 3H), 0.75 (d, 3H).

Example 67.1C tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)benzoate(racemate)

120 mg (333 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate) and 70.7 mg (366 μmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. The crudeproduct was purified by flash chromatography (silica gel 50,cyclohexane/ethyl acetate mixtures). Yield: 134 mg (75% of theory)

LC/MS [Method 1]: R_(t)=1.29 min; MS (ESIpos): m/z=536 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.0 (s, 1H), 8.00 (d, 1H), 7.88 (d,2H), 7.78 (d, 2H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.63 (s, 1H), 6.56 (s,1H), 5.52 (d, 1H), 3.69 (s, 3H), 2.61-2.55 (m, 1H), 1.54 (s, 9H), 1.08(d, 3H), 0.82 (d, 3H).

Example 67.2A Methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-2-methylbenzoate(racemate)

120 mg (333 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate) and 60.4 mg (366 μmol, 1.1 eq.) of methyl4-amino-2-methylbenzoate were reacted according to General Method 5A.The crude product was purified by flash chromatography (silica gel 50,cyclohexane/ethyl acetate mixtures). Yield: 155 mg (88% of theory)

LC/MS [Method 1]: R_(t)=1.17 min; MS (ESIpos): m/z=508 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.00 (d, 1H), 7.85 (d,1H), 7.77-7.71 (m, 2H), 7.66-7.59 (m, 3H), 6.56 (s, 1H), 5.51 (d, 1H),3.80 (s, 3H), 3.69 (s, 3H), 2.69 (s, 3H), 1.08 (d, 3H), 0.82 (d, 3H).

Example 67.3A Ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-1H-benzimidazole-2-carboxylate(racemate)

100 mg (277 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate), 57 mg (277 μmol, 1.0 eq.) of ethyl6-amino-1H-benzimidazole-2-carboxylate, 39.4 mg (277 μmol) of Oxima and42.9 μl (277 μmol) of DIC in 5.4 ml of dimethylformamide were reactedaccording to General Method 5B. The crude product was purified by flashchromatography (silica gel 50, cyclohexane/ethyl acetate mixtures).Yield: 139 mg (91% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=548 (M+H)⁺.

Example 68.1A tert-Butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate)

300 mg (796 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) and 231 mg (876 μmol, 1.1 eq.) of tert-butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate werereacted according to General Method 5A. The crude product was purifiedby flash chromatography (silica gel 50, cyclohexane/ethyl acetatemixtures). Yield: 229 mg (46% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=622 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.53 (d, 1H), 8.01-7.98(m, 1H), 7.75-7.71 (m, 3H), 7.53 (s, 1H), 7.49 (dd, 1H), 6.53 (s, 1H),5.79 (dd, 1H), 3.69 (s, 3H), 3.46 (s, 3H), 3.44-3.38 (m, 1H), 3.31 (s,1H), 3.21 (s, 3H), 2.48-2.36 (m, 2H), 1.60 (s, 9H).

Example 68.2A Ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-1H-indole-2-carboxylate(racemate)

100 mg (265 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate), 54.2 mg (265 μmol, 1.0 eq.) of ethyl6-amino-1H-indole-2-carboxylate, 37.7 mg (265 μmol) of Oxima and 41.4 μl(265 μmol) of DIC in 5.5 ml of dimethylformamide were reacted accordingto General Method 5B. The crude product was purified by preparative HPLC(column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water/0.1%formic acid and acetonitrile/0.1% formic acid, gradient 10% acetonitrileto 90% acetonitrile). Yield: 85 mg (54% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=563 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.8 (d, 1H), 10.5 (s, 1H), 8.04 (br.s, 1H), 8.00 (d, 1H), 7.76-7.72 (m, 2H), 7.58 (d, 1H), 7.56 (s, 1H),7.23 (dd, 1H), 7.11-7.08 (m, 1H), 6.53 (s, 1H), 5.80 (dd, 1H), 4.32 (q,2H), 3.70 (s, 3H), 3.43-3.26 (m, 2H), 3.22 (s, 3H), 2.47-2.36 (m, 2H),1.33 (t, 3H).

Example 68.3A Ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-5-methoxy-1H-indole-2-carboxylate(racemate)

150 mg (398 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) and 103 mg (438 μmol, 1.1 eq.) of ethyl6-amino-5-methoxy-1H-indole-2-carboxylate were reacted according toGeneral Method 5A. The crude product was purified by preparative HPLC(column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: water andacetonitrile, gradient 10% acetonitrile to 90% acetonitrile). Yield: 87mg (36% of theory)

LC/MS [Method 1]: R_(t)=1.13 min; MS (ESIpos): m/z=593 (M+H)⁺,

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=11.7 (d, 1H), 9.43 (s, 1H), 8.26 (s,1H), 8.00 (d, 1H), 7.76-7.72 (m, 2H), 7.51 (s, 1H), 7.20 (s, 1H),7.04-7.03 (m, 1H), 6.58 (s, 1H), 5.79 (dd, 1H), 4.32 (q, 2H), 3.86 (s,3H), 3.69 (s, 3H), 3.45-3.34 (m, 2H), 3.25 (s, 3H), 2.57-2.46 (m, 1H),2.43-2.34 (m, 1H), 1.33 (t, 3H).

Example 69.1A tert-Butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoate(racemate)

416 mg (1.00 mmol) of tert-butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate inthe presence of 0.95 ml (0.95 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 326 mg (1.58 mmol, 2.0eq.) of isobutyl trifluoromethanesulphonate were reacted according toGeneral Method 7B. Yield: 139 mg (purity 85%, 34% of theory)

LC/MS [Method 1]: R_(t)=1.27 min; MS (ESIpos): m/z=435 (M+H)⁺.

Example 69.1B2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoicacid (racemate)

139 mg (purity 85%, 0.27 mmol) of tert-butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 87 mg (84% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=379 (M+H)⁺.

Example 69.1C tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate(racemate)

87 mg (0.23 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoicacid (racemate) and 49 mg (0.25 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 45mg (35% of theory)

LC/MS [Method 1]: R_(t)=1.40 min; MS (ESIpos): m/z=554 (M+H)⁺.

Example 70.1A tert-Butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate(racemate)

300 mg (0.79 mmol) of tert-butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate inthe presence of 0.95 ml (0.95 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 207 mg (0.79 mmol, 1.0eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate werereacted according to General Method 7B. Yield: 244 mg (purity 92%, 58%of theory)

LC/MS [Method 8]: R_(t)=1.53 min; MS (ESIpos): m/z=435(M+H—COO-tert-butyl)⁺.

Example 70.1B2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoicacid (racemate)

244 mg (purity 92%, 0.46 mmol) of tert-butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 237 mg (purity 84%, quant.)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=435 (M+H)⁺.

Example 70.1C tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoate(racemate)

237 mg (purity 84%, 0.46 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoicacid (racemate) and 97 mg (0.50 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 142mg (purity 81%, 41% of theory)

LC/MS [Method 1]: R_(t)=1.35 min; MS (ESIneg): m/z=608 (M−H)⁻.

Example 71.1A tert-Butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetate

5.43 g (purity 80%, 14.4 mmol) of4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and1.2 eq. of tert-butyl bromoacetate in the presence of 1.5 eq. ofpotassium carbonate were reacted according to General Method 4B at 100°C. Yield: 3.64 g (61% of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=416 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.57 (dd, 1H), 7.45 (d, 1H), 7.43 (s,1H), 7.30 (d, 1H), 7.13 (t, 1H), 6.35 (s, 1H), 4.58 (s, 2H), 3.56 (s,3H), 1.44 (s, 9H).

Example 71.1B tert-Butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoate(racemate)

416 mg (1.00 mmol) of tert-butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetatein the presence of 1.20 ml (1.20 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 309 mg (1.50 mmol, 1.5eq.) of isobutyl trifluoromethanesulphonate were reacted according toGeneral Method 7B. Yield: 370 mg (75% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=472 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.57 (dd, 1H), 7.49 (d, 1H), 7.29 (d,1H), 7.25 (s, 1H), 7.10 (t, 1H), 6.36 (s, 1H), 5.29 (dd, 1H), 3.59 (s,3H), 2.19-2.08 (m, 1H), 1.91-1.81 (m 1H), 1.43-1.33 (m, 1H), 1.40 (s,9H), 0.9 (dd, 6H).

Example 71.1C2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridine-1(2H)-yl}-4-methylpentanoicacid (racemate)

370 mg (0.75 mmol) of tert-butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 319 mg (purity 91%, 93% of theory)

LC/MS [Method 8]: R_(t)=1.27 min; MS (ESIpos): m/z=416 (M+H)⁺.

Example 71.1D tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoyl)amino]benzoate(racemate)

319 mg (purity 91%, 0.70 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoicacid (racemate) and 148 mg (0.77 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 263mg (purity 88%, 56% of theory)

LC/MS [Method 1]: R_(t)=1.37 min; MS (ESIpos): m/z=591 (M+H)⁺.

Example 72.1A tert-Butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoate(racemate)

312 mg (0.75 mmol) of tert-butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetatein the presence of 0.90 ml (0.90 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 312 mg (1.50 mmol, 1.5eq.) of 2-methoxyethyl trifluoromethanesulphonate were reacted accordingto General Method 7B. Yield: 201 mg (purity 91%, 51% of theory)

LC/MS [Method 8]: R_(t)=1.40 min; MS (ESIpos): m/z=418(M+H—COO-tert-butyl)⁺.

Example 72.1B2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoicacid (racemate)

201 mg (purity 91%, 0.39 mmol) of tert-butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 212 mg (purity 82%, quant.)

LC/MS [Method 8]: R_(t)=1.11 min; MS (ESIpos): m/z=418 (M+H)⁺.

Example 72.1C tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]benzoate(racemate)

90 mg (purity 77%, 0.17 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoicacid (racemate) and 35 mg (0.18 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 66mg (67% of theory)

LC/MS [Method 8]: R_(t)=1.52 min; MS (ESIneg): m/z=591 (M−H)⁻.

Example 72.2A tert-Butyl6-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate)

113 mg (purity 82%, 0.26 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoicacid (racemate) and 79 mg (0.29 mmol, 1.1 eq.) of tert-butyl6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate werereacted according to General Method 5A. Yield: 132 mg (73% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIpos): m/z=663 (M+H)⁺.

Example 73.1A tert-Butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoate(racemate)

416 mg (1.00 mmol) of tert-butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetatein the presence of 1.20 ml (1.20 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 393 mg (1.50 mmol, 1.5eq.) of 2-(trifluoromethoxy)ethyl trifluoromethanesulphonate werereacted according to General Method 7B. Yield: 327 mg (62% of theory)

LC/MS [Method 1]: R_(t)=1.23 min; MS (ESIpos): m/z=528 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.57 (dd, 1H), 7.45 (d, 1H), 7.32 (s,1H), 7.30 (d, 1H), 7.09 (t, 1H), 6.37 (s, 1H), 5.11 (dd, 1H), 4.21-4.13(m, 1H), 4.05-3.95 (m, 1H), 3.57 (s, 3H), 1.40 (s, 9H).

Example 73.1B2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoicacid (racemate)

327 mg (0.62 mmol) of tert-butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 290 mg (purity 93%, 92% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=472 (M+H)⁺.

Example 73.1C tert-Butyl4-{[2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoate(racemate)

290 mg (purity 93%, 0.57 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoicacid (racemate) and 122 mg (0.63 mmol, 1.1 eq.) of tert-butyl4-aminobenzoate were reacted according to General Method 5A. Yield: 195mg (50% of theory)

LC/MS [Method 1]: R_(t)=1.33 min; MS (ESIpos): m/z=647 (M+H)⁺.

Example 74.1A (2R)-Tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate

568 mg (purity 69%, 3.48 mmol) of (2R)-tetrahydro-2H-pyran-2-ylmethanoland 0.71 ml (4.18 mmol, 1.2 eq.) of trifluoromethanesulphonic anhydridein the presence of 0.58 ml (4.18 mmol, 1.2 eq.) of triethylamine werereacted according to General Method 8A. The crude product was reacted inthe next step without further purification.

Example 74.1B tert-Butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2)

333 mg (0.80 mmol) of tert-butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetatein the presence of 0.96 ml (0.96 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) and 426 mg (purity 70%,1.20 mmol, 1.5 eq.) of (2R)-tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate were reacted according to General Method 7B.Yield: 85 mg (purity 94%, 19% of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=514 (M+H)⁺.

Example 74.1C2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

85 mg (purity 94%, 0.16 mmol) of tert-butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 83 mg (purity 85%, 99%of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=458 (M+H)⁺.

Example 74.1D tert-Butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

82 mg (purity 85%, 0.15 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2) and 32 mg(0.17 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reactedaccording to General Method 5A. Yield: 67 mg (70% of theory)

LC/MS [Method 1]: diastereomer 1: R_(t)=1.35 min; MS (ESIpos): m/z=633(M+H)⁺; diastereomer 2: R_(t)=1.36 min; MS (ESIpos): m/z=633 (M+H)⁺.

Example 75.1A tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoate(racemate)

150 mg (0.43 mmol, 1.0 eq.) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 152 mg (0.65 mmol, 1.5 eq.) of tert-butyl2-fluoro-4-aminophenylcarboxylate were reacted according to GeneralMethod 5C. The crude product was purified by normal phase chromatography(mobile phase: cyclohexane/ethyl acetate 20%-50% mixtures). Yield: 250mg (purity 93%, 99% of theory)

LC/MS [Method 8]: R_(t)=1.51 min; MS (ESIneg): m/z=538 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.95 (s, 1H), 8.02-7.97 (m, 1H),7.81 (t, 1H), 7.75-7.66 (m, 3H), 7.47 (s, 1H), 7.42 (dd, 1H), 6.54 (s,1H), 5.59 (dd, 1H), 3.69 (s, 3H), 2.25-2.13 (m, 2H), 1.53 (s, 9H), 0.90(t, 3H).

Example 75.2A tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-3-fluorobenzoate(racemate)

100 mg (0.29 mmol, 1.0 eq.) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 91 mg (0.43 mmol, 1.5 eq.) of tert-butyl4-amino-3-fluorobenzoate were reacted according to General Method 5C.The crude product was purified by normal phase chromatography (mobilephase: cyclohexane/ethyl acetate 35%-50% mixtures). Yield: 126 mg (81%of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=540 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.56 (s, 1H), 8.15-8.08 (m, 1H),8.02-7.97 (m, 1H), 7.76-7.68 (m, 4H), 7.46 (s, 1H), 6.54 (s, 1H), 5.79(dd, 1H), 3.68 (s, 3H), 2.25-2.15 (m, 2H), 1.54 (s, 9H), 0.91 (t, 3H).

Example 75.3A tert-Butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,5-difluorobenzoate(racemate)

150 mg (0.43 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 154 mg (0.61 mmol, 1.4 eq.) of tert-butyl4-amino-2,5-difluorobenzoate were reacted according to General Method5B. The crude product was purified by normal phase chromatography(mobile phase: cyclohexane/ethyl acetate 20-40% mixtures). Yield: 180 mg(71% of theory)

LC/MS [Method 1]: R_(t)=1.31 min; MS (ESIpos): m/z=558 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.75 (s, 1H), 8.05 (dd, 1H),8.01-7.97 (m, 1H), 7.76-7.71 (m, 2H), 7.69 (dd, 1H), 7.45 (s, 1H), 6.55(s, 1H), 5.84-5.78 (m, 1H), 3.69 (s, 3H), 2.24-2.15 (m, 2H), 1.53 (s,9H), 0.90 (t, 3H).

Example 75.4A Methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,3-difluorobenzoate(racemate)

100 mg (0.29 mmol, 1.0 eq.) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 85 mg (0.43 mmol, 1.5 eq.) of methyl4-amino-2,3-difluorobenzoate were reacted according to General Method5C. The crude product was purified by normal phase chromatography(mobile phase: cyclohexane/ethyl acetate 35-50% mixtures). Yield: 113 mg(76% of theory)

LC/MS [1]: R_(t)=1.08 min; MS (ESIpos): m/z=516 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.77 (s, 1H), 8.02-7.97 (m, 1H),7.96-7.89 (m, 1H), 7.76-7.66 (m, 3H), 7.45 (s, 1H), 6.55 (s, 1H), 5.79(dd, 1H), 3.86 (s, 3H), 3.68 (s, 3H), 2.26-2.12 (m, 2H), 0.91 (t, 3H).

Example 75.5A Methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,6-difluorobenzoate(racemate)

At 60-70° C., 110 μl (0.46 mmol, 4 eq.) of T3P (50% in ethyl acetate)were added dropwise to a solution of 46 mg (0.13 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 51 mg (0.27 mmol, 2 eq.) of methyl4-amino-2,6-difluorobenzoate in 1 ml of pyridine. The reaction mixturewas heated to 90° C., stirred at 90° C. for 30 min and cooled to RT, andwater and ethyl acetate were added. After phase separation, the aqueousphase was extracted with ethyl acetate. The combined organic phases werewashed with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was purified by normal phase chromatography (mobile phase:cyclohexane/ethyl acetate 10-50% mixtures). Yield: 54 mg (79% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=516 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.06 (s, 1H), 8.02-7.98 (m, 1H),7.75-7.72 (m, 2H), 7.50-7.44 (m, 3H), 6.55 (s, 1H), 5.55 (dd, 1H), 3.85(s, 3H), 3.69 (s, 3H), 2.24-2.14 (m, 2H), 0.90 (t, 3H).

Example 76.1A tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate(racemate)

Under argon and at −78° C., 14.0 ml (1.0M in THF, 14.0 mmol, 1.05 eq.)of bis(trimethylsilyl)lithium amide were added dropwise to a solution of5.0 g (13.3 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in100 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for 15min. 2.6 g (14.7 mmol, 1.1 eq.) of neat ethyl trifluoromethanesulphonatewere then added dropwise. The cooling bath was removed and the reactionmixture was stirred at RT for another 1 h. The reaction mixture wascooled to 0° C., and saturated aqueous ammonium chloride solution wasadded. After phase separation, the aqueous phase was extracted twicewith methyl tert-butyl ether. The combined organic phases were dried(sodium sulphate), filtered and concentrated under reduced pressure. Thecrude product was then purified by flash chromatography (340 g of silicagel, mobile phase: cyclohexane/ethyl acetate mixtures 8:1, 4:1). Theproduct-containing fractions were combined and concentrated underreduced pressure. The residue was dissolved in hot methyl tert-butylether and the solution was left to stand without any cover, and after 10min the mixture had crystallized almost completely. The crystals werefiltered off and washed twice with methyl tert-butyl ether. The combinedfiltrates were concentrated under reduced pressure and the residue wasre-crystallized as described. The two crystal batches were combined anddried under reduced pressure. Yield: 4.2 g (78% of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=403 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.99 (d, 1H), 7.77-7.70 (m, 2H), 7.36(s, 1H), 6.50 (s, 1H), 5.03 (dd, 1H), 3.64 (s, 3H), 2.19-2.06 (m, 2H),1.40 (s, 9H), 0.85 (t, 3H).

Example 76.1B Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate(racemate)

Under argon and at RT, 476 mg (2.9 mmol, 1.0 eq.) of ethyl4-aminobenzoate and 41 mg (0.29 mmol, 0.1 eq.) of Oxima and then,dropwise, 452 μl (2.9 mmol, 1.0 eq.) of N,N′-diisopropylcarbodiimide(DIC) were added to a solution of 1.0 g (2.9 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) in 10 ml of dimethylformamide. The reaction mixture wasstirred at 40-45° C. for 3 h and cooled to RT, methyl tert-butyl etherand water were added and the mixture was stirred vigorously for 10 min,resulting in the formation of a precipitate. The precipitate wasfiltered off, washed twice with water and methyl tert-butyl ether anddried under reduced pressure (precipitate 1). After phase separation ofthe combined filtrates, the aqueous phase was extracted once with methyltert-butyl ether. The combined organic phases were washed once withsaturated aqueous sodium chloride solution, dried (sodium sulphate),filtered and concentrated under reduced pressure. The residue wastriturated with methyl tert-butyl ether, filtered, washed twice withmethyl tert-butyl ether and dried under reduced pressure. Thisprecipitate was stirred in aqueous hydrochloric acid (1N) for 10 min,filtered off, washed twice with water and once with acetonitrile anddried under reduced pressure (precipitate 2). Yield: precipitate 1: 1.12g (79% of theory), precipitate 2: 127 mg (still contains1,3-diisopropylurea according to ¹H NMR)

LC/MS [Method 1]: R_(t)=1.11 min; MS (ESIneg): m/z=492 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.82 (s, 1H), 8.00 (d, 1H), 7.93 (d,2H), 7.81-7.70 (m, 4H), 7.49 (s, 1H), 6.54 (s, 1H), 5.63 (dd, 1H), 4.29(q, 2H), 3.69 (s, 3H), 2.26-2.11 (m, 2H), 1.31 (t, 3H), 0.91 (t, 3H).

Example 77.1A (1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methanol

At room temperature, a solution of 500 mg (3.78 mmol) oftetrahydrothiopyran-4-ylmethanol in 10 ml of methanol was added withcooling to a solution of 1.86 g (8.70 mmol) of sodium periodate in 18 mlof water. The mixture was stirred at 60° C. for another 1 h, andmethanol was then distilled off under reduced pressure and the resultingprecipitate was filtered off with suction. The aqueous phase thatremained was extracted twice with 10 ml of diethyl ether, twice with 10ml of dichloromethane, twice with 10 ml of dichloromethane/methanol(1:1, v/v) and, after addition of 5 ml of water, twice with 10 ml ofethyl acetate. The combined organic phases were dried over sodiumsulphate and filtered, and the solvent was removed under reducedpressure. The aqueous phase was extracted four more times with 20 ml of2-methyltetrahydrofuran. The combined organic phases were dried oversodium sulphate and filtered, and the solvent was removed under reducedpressure. Combined yield: 406 mg (65% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.60-3.56 (m, 2H), 3.13-3.06 (m, 2H),3.02-2.93 (m, 2H), 2.24-2.16 (m, 2H), 1.95-1.83 (m, 2H), 1.80-1.63 (m,1H), 1.50 (t, 1H).

Example 77.1B (1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methyltrifluoromethanesulphonate

At −78° C., a solution of 380 mg (2.31 mmol) of(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methanol and 355 μl (2.55 mmol)of triethylamine in 3 ml of dichloromethane was added dropwise to 428 μl(2.55 mmol) of trifluoromethanesulphonic anhydride in 3 ml ofdichloromethane such that the internal temperature did not exceed −50°C. The mixture was stirred at −78° C. for another 30 min andspontaneously warmed to RT. The reaction mixture was diluted with 30 mlof methyl tert-butyl ether and washed with saturated aqueous ammoniumchloride solution, saturated aqueous sodium chloride solution andsaturated aqueous sodium bicarbonate solution, dried over magnesiumsulphate, filtered and concentrated at 25° C. and a pressure of ≧100mbar. Yield: 503 mg (73% of theory)

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=4.40 (d, 2H), 3.17-3.09 (m, 2H),3.07-2.98 (m, 2H), 2.25-2.17 (m, 2H), 2.16-1.95 (m, 3H).

Example 77.1C tert-Butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoate(racemate)

421 mg (1.13 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 500mg (1.69 mmol) of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyltrifluoromethanesulphonate and 1.46 ml (1.46 mmol) ofbis(trimethylsilyl)lithium amide (1M in THF) in 15 ml of THF werereacted according to General Method 7B. Aqueous work-up gave the titlecompound. Yield: 862 mg (purity 91%, quant.)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=521 (M+H)⁺

Example 77.1D2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoicacid (racemate)

860 mg (1.65 mmol) of tert-butyl2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoate(racemate) in 16.6 ml of dichloromethane and 4.77 ml (61.9 mmol) of TFAwere reacted according to General Method 6A. Yield: 1.18 g (purity 72%,quant.)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIneg): m/z=463 (M−H)⁻

Example 77.1E Ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoyl}amino)benzoate(racemate)

768 mg (1.19 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoicacid (racemate, purity 72%), 786 mg (4.76 mmol) of ethyl4-aminobenzoate, 67.6 mg (476 μmol) of Oxima and 741 μl (4.76 mmol) ofDIC in 11.5 ml of dimethylformamide were reacted according to GeneralMethod 5B. Preparative HPLC (acetonitrile/water gradient) gave the titlecompound. Yield: 331 mg (45% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=612 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.8 (s, 1H), 8.00 (d, 1H), 7.95 (d,2H), 7.80-7.71 (m, 4H), 7.50 (s, 1H), 6.55 (s, 1H), 5.85 (dd, 1H), 4.29(q, 2H), 3.70 (s, 3H), 3.14-2.95 (m, 4H), 2.37-2.28 (m, 1H), 2.15-2.02(m, 3H), 1.81-1.66 (m, 2H), 1.56-1.43 (m, 1H), 1.31 (t, 3H).

Example 78.1A 2-[(Benzyloxy)methyl]tetrahydro-2H-pyran (racemate)

At 0° C., a solution of 25.0 g (215 mmol) oftetrahydro-2H-pyran-2-ylmethanol (racemate) in 500 ml of THF was slowlyadded dropwise to a suspension of 9.47 g (237 mmol, 60% in mineral oil)of sodium hydride in 500 ml of THF, and after the addition had ended,the mixture was stirred at 0° C. for another 30 min 25.7 ml (215 mmol)of benzyl bromide were then added, and the mixture was stirred at 0° C.for another 30 min and at room temperature for another 1 h. The reactionwas terminated by addition of 200 ml of saturated aqueous ammoniumchloride solution, and the phases were separated. The aqueous phase wasextracted twice with 200 ml of methyl tert-butyl ether. The combinedorganic phases were dried over magnesium sulphate and filtered, and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography (ethyl acetate/cyclohexane gradient,340 g silica cartridge, flow rate 100 ml/min), giving the titlecompound. Yield: 41.9 g (94% of theory)

LC/MS [Method 3]: R_(t)=2.18 min; MS (ESIpos): m/z=207 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=7.37-7.25 (m, 5H), 4.47 (s, 2H),3.87-3.81 (m, 1H), 3.47-3.28 (m, 4H), 1.80-1.72 (m, 1H), 1.58-1.37 (m,4H), 1.25-1.13 (m, 1H).

Example 78.1B (R)-2-[(Benzyloxy)methyl]tetrahydro-2H-pyran

Enantiomer separation of 41.9 g of the racemate from Example 78.1A gave16.7 g of the title compound Example 78.1B (enantiomer 1): Chiral HPLC:R_(t)=5.28 min; 99% ee, purity 93%.

Optical rotation: [α]₅₈₉ ^(20.0)=+14.9° (c 0.43 g/100 cm³, CHCl₃)

Separation method: column: OD-H 5 μm 250 mm×20 mm; mobile phase: 95%isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UVdetection: 210 nm.

Analysis: Column: OD-H 5 μm 250 mm×4.6 mm; mobile phase: 95% isohexane,5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

Example 78.2B (S)-2-[(Benzyloxy)methyl]tetrahydro-2H-pyran

Enantiomer separation of 41.9 g of the racemate from Example 78.1A gave17.0 g of the title compound Example 78.2B (enantiomer 2): Chiral HPLC:R_(t)=7.36 min; 96% ee, purity 96%.

Optical rotation: [α]₅₈₉ ^(20.0)=13.9° (c 0.61 g/100 cm³, CHCl₃)

Separation method: Column: OD-H 5 μm 250 mm×20 mm; mobile phase: 95%isohexane, 5% 2-propanol; temperature: 25° C.; flow rate: 25 ml/min; UVdetection: 210 nm.

Analysis: Column: OD-H 5 μm 250 mm×4.6 mm; mobile phase: 95% isohexane,5% 2-propanol; flow rate: 1 ml/min; UV detection: 220 nm.

Example 78.1C (2R)-Tetrahydro-2H-pyran-2-ylmethanol

2.0 g of palladium on carbon (10%) were added to a solution of 16.7 g(75.3 mmol) of (R)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran (purity 93%)in 150 ml of ethanol, and the mixture was hydrogenated under standardconditions overnight. The reaction mixture was then filtered throughCelite and another 1.5 g of palladium on carbon (10%) were added. Themixture was hydrogenated for another 72 h. The reaction mixture wasfiltered through Celite, the filter cake was washed with ethanol, andthe filtrate was concentrated under reduced pressure. The residue waspurified chromatographically (silica, ethyl acetate/cyclohexanegradient) and the product fractions were freed from the solvent at <35°C. and >80 mbar. Yield: 5.47 g (63% of theory)

Optical rotation: [α]₅₈₉ ^(20.0)=9.4° (c 0.4 g/100 cm³, CHCl₃)

GC/MS [Method 9]: R_(t)=2.16 min; MS: m/z=116 (M)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.51 (t, 1H), 3.87-3.81 (m, 1H),3.37-3.18 (m, 4H), 1.80-1.71 (m, 1H), 1.59-1.50 (m, 1H), 1.49-1.36 (m,3H), 1.19-1.05 (m, 1H).

Example 78.2C (2S)-Tetrahydro-2H-pyran-2-ylmethanol

3.51 g (3.30 mmol) of palladium on carbon (10%) were added to a solutionof 17.0 g (82.4 mmol) of (S)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran(96% ee, purity 96%) in 120 ml of ethanol, and the mixture washydrogenated at room temperature and under standard pressure overnight.Another 1.75 g (1.65 mmol) of palladium on carbon (10%) were then added,and the mixture was hydrogenated at room temperature for a further 72 h.Subsequently, the reaction mixture was filtered through Celite and thefiltrate was concentrated. The residue was purified chromatographically(silica, dichloromethane/methanol gradient) and the product fractionswere freed from the solvent at <25° C. and >50 mbar. Yield: 8.23 g (86%of theory)

Optical rotation: [α]₅₈₉ ^(20.0)=9.1° (c 0.36 g/100 cm³, CHCl₃), cf. A.Aponick, B. Biannic, Org. Lett. 2011, 13, 1330-1333.

GC/MS [Method 7]: R_(t)=1.82 min; MS: m/z=116 (M)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.51 (t, 1H), 3.87-3.81 (m, 1H),3.37-3.18 (m, 4H), 1.80-1.71 (m, 1H), 1.59-1.50 (m, 1H), 1.49-1.36 (m,3H), 1.19-1.05 (m, 1H).

Example 79.1A (2S)-Tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate

330 mg (2.84 mmol) of (2S)-tetrahydro-2H-pyran-2-ylmethanol were reactedwith 0.57 ml (3.41 mmol, 1.2 eq.) of trifluoromethanesulphonic anhydridein the presence of 0.48 ml (3.41 mmol, 1.2 eq.) of triethylamineaccording to General Method 8A. The crude product was reacted in thenext step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.32 (dd, 1H), 4.18 (dd, 1H),4.00-3.92 (m, 1H), 3.60-3.52 (m, 1H), 3.48-3.39 (m, 1H), 1.85-1.74 (m,1H), 1.56-1.41 (m, 4H), 1.28-1.14 (m, 1H).

Example 79.1B tert-Butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2)

237 mg (0.55 mmol) of tert-butyl{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}acetatein the presence of 0.72 ml (0.72 mmol, 1.3 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) were reacted with 274 mg(1.11 mmol, 2.0 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate according to General Method 7B. Yield: 130 mg(45% of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=514 (M+H)⁺.

Example 79.1C2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

311 mg (purity 90%, 0.55 mmol) of tert-butyl2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 312 mg (purity 87%,quant.)

LC/MS [Method 2]: diastereomer 1: R_(t)=2.86 min; MS (ESIpos): m/z=458(M+H)⁺; diastereomer 2: R_(t)=2.92 min; MS (ESIpos): m/z=458 (M+H)⁺.

Example 79.1D Ethyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

Two fractions, 312 mg (purity 87%, 0.59 mmol) and 86 mg (0.19 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2), werereacted with in total 202 mg (1.23 mmol, 1.6 eq.) of ethyl4-aminobenzoate according to General Method 5B. Yield: 315 mg (83% oftheory)

LC/MS [Method 1]: diastereomer 1: R_(t)=1.20 min; MS (ESIpos): m/z=605(M+H)⁺; diastereomer 2: R_(t)=1.22 min; MS (ESIpos): m/z=605 (M+H)⁺.

Example 80.1A tert-Butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2)

570 mg (1.46 mmol) of tert-butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.75 ml (1.75 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) were reacted with 707 mg(purity 87%, 2.48 mmol, 1.7 eq.) of (2S)-tetrahydro-2H-pyran-2-ylmethyltrifluoromethanesulphonate according to General Method 7B. Yield: 396 mg(57% of theory)

LC/MS [Method 1]: R_(t)=1.25 min; MS (ESIpos): m/z=421(M+H—COO-tert-butyl)⁺.

Example 80.1B2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

396 mg (0.83 mmol) of tert-butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 6A. Yield: 396 mg (quant.)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=421 (M+H)⁺.

Example 80.1C tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2)

396 mg (0.90 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2,9-tetrahydro-2H-pyran-2-yl]propanoicacid (mixture of enantiomerically pure diastereomers 1 and 2) werereacted with 192 mg (0.99 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoateaccording to General Method 5A. Yield: 364 mg (68% of theory)

LC/MS [Method 1]: diastereomer 1: R_(t)=1.32 min; MS (ESIpos): m/z=596(M+H)⁺; diastereomer 2: R_(t)=1.34 min; MS (ESIpos): m/z=596 (M+H)⁺.

Example 81.1A tert-Butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate(racemate)

500 mg (1.32 mmol) of tert-butyl[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]acetate inthe presence of 1.58 ml (1.58 mmol, 1.2 eq.) ofbis(trimethylsilyl)lithium amide (1M in THF) were reacted with 556 mg(purity 74%, 1.98 mmol, 1.5 eq.) of 2-methoxyethyltrifluoromethanesulphonate according to General Method 7B. Yield: 455 mg(purity 80%, 63% of theory)

LC/MS [Method 1]: R_(t)=1.16 min; MS (ESIpos): m/z=381(M+H—COO-tert.-butyl)⁺.

Example 81.1B2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid

455 mg (purity 80%, 0.83 mmol) of tert-butyl2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoate(racemate) were hydrolysed with TFA according to General Method 6A.Yield: 417 mg (purity 76%, quant.)

LC/MS [Method 8]: Rt=0.86 min; MS (ESIpos): m/z=381 (M+H)⁺.

Example 81.1C tert-Butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate(racemate)

417 mg (purity 76%, 0.83 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) were reacted with 177 mg (0.91 mmol, 1.1 eq.) oftert-butyl 4-aminobenzoate according to General Method 5A. Yield: 438 mg(92% of theory)

LC/MS [Method 1]: R_(t)=1.24 min; MS (ESIpos): m/z=556 (M+H)⁺.

WORKING EXAMPLES General Method 1 Amide Coupling Using HATU/DIEA

Under argon and at RT, the appropriate amine (1.1 eq.),N,N-diisopropylethylamine (DIEA) (2.2 eq.) and a solution of HATU (1.2eq.) in a little DMF were added to a solution of the appropriatecarboxylic acid (1.0 eq.) in dimethylformamide (about 12 ml/mmol). Thereaction mixture was stirred at RT. After addition of water/ethylacetate and phase separation, the organic phase was washed with waterand with saturated aqueous sodium chloride solution, dried (sodiumsulphate), filtered and concentrated under reduced pressure. The crudeproduct was then purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient or water/methanol gradient).

General Method 2 Hydrolysis of a Tert-Butyl Ester or a Boc-ProtectedAmine Using TFA

At RT, TFA (20 eq.) was added to a solution of the appropriatetert-butyl ester derivative or a Boc-protected amine (1.0 eq.) indichloromethane (about 25 ml/mmol), and the mixture was stirred at RTfor 1-8 h. Subsequently, the reaction mixture was concentrated underreduced pressure. The residue was co-evaporated repeatedly withdichloromethane and/or toluene. The crude product was then purified bypreparative RP-HPLC (mobile phase: acetonitrile/water gradient orwater/methanol gradient).

General Method 3 Hydrolysis of a Methyl or Ethyl Ester with LithiumHydroxide

At RT, lithium hydroxide (2-4 eq.) was added to a solution of theappropriate ester (1.0 eq.) in a mixture of tetrahydrofuran/water (3:1,about 15 ml/mmol), and the mixture was stirred at RT. The reactionmixture was then adjusted to pH 1 using aqueous hydrochloric acidsolution (1N). After addition of water/ethyl acetate, the aqueous phasewas extracted three times with ethyl acetate. The combined organicphases were dried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified either by flashchromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetatemixtures or dichloromethane/methanol mixtures) or by preparative HPLC(Reprosil C18, water/acetonitrile gradient or water/methanol gradient).

General Method 4 Hydrolysis of a Methyl or Ethyl Ester with CaesiumCarbonate

Caesium carbonate (2 eq.) was added to a solution of the appropriatemethyl or ethyl ester (1 eq.) in a mixture of methanol/water (4/1,0.05-0.2M), and the resulting suspension was stirred at RT to 60° C. for3-8 h. The reaction mixture was cooled to RT if required and adjusted topH 3 using aqueous hydrochloric acid (1N). Methanol was removed at 30°C. under reduced pressure. The aqueous phase was extracted with ethylacetate. The combined organic phases were dried (sodium sulphate ormagnesium sulphate), filtered and concentrated under reduced pressure.The residue was purified by means of preparative HPLC.

General Method 5 Amide Coupling Using OXIMA/DIC

N,N′-Diisopropylcarbodiimide (DIC) (1 eq.) was added dropwise to adegassed solution of the appropriate carboxylic acid (1 eq.), aniline (1eq.) and ethyl hydroxyiminocyanoacetate (Oxima) (0.1-1 eq.) indimethylformamide (0.1M), and the resulting reaction solution wasstirred at RT-40° C. for 8-24 h. The solvent was removed under reducedpressure. The residue was either admixed with water and the desiredproduct was filtered off or purified by normal phase chromatography(cyclohexane/ethyl acetate gradient) or preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

General Method 6 Amide Coupling Using T3P/DIEA

Under argon and at 0° C., N,N-diisopropylethylamine (3 eq.) andpropylphosphonic anhydride (T3P, 50% in dimethylformamide, 3 eq.) wereadded dropwise to a solution of the carboxylic acid and the appropriateamine (1.1-1.5 eq.) in dimethylformamide (0.15-0.05 mmol). The reactionmixture was stirred at RT and then concentrated under reduced pressure.After addition of water/ethyl acetate and phase separation, the aqueousphase was extracted twice with ethyl acetate. The combined organicphases were dried (sodium sulphate or magnesium sulphate), filtered andconcentrated under reduced pressure. The crude product was then purifiedeither by flash chromatography (silica gel 60, mobile phase:cyclohexane/ethyl acetate mixtures or dichloromethane/methanol mixtures)or by preparative HPLC (Reprosil C18, water/acetonitrile gradient orwater/methanol gradient).

General Method 7 Amide Coupling Using T3P/Pyridine

Under argon and at 0° C., propylphosphonic anhydride (T3P, 50% in ethylacetate, 4 eq.) was added dropwise to a solution of the carboxylic acid(1 eq.) and the appropriate amine (1.5 eq.) in pyridine (0.15-0.05 M).This mixture was heated to 90° C. and stirred at 90° C. for 1-20 h. Thereaction mixture was cooled to RT, and water and ethyl acetate wereadded. After phase separation, the aqueous phase was extracted withethyl acetate. The combined organic phases were washed with aqueousbuffer solution (pH 5), with saturated aqueous sodium bicarbonatesolution and with saturated aqueous sodium chloride solution, dried(sodium sulphate or magnesium sulphate), filtered and concentrated underreduced pressure. The crude product was then optionally purified eitherby normal phase chromatography (mobile phase: cyclohexane/ethyl acetatemixtures or dichloromethane/methanol mixtures) or by preparative RP-HPLC(water/acetonitrile gradient or water/methanol gradient).

Example 12-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]propanamide(racemate)

65 mg (purity 83%, 0.18 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 1.2 eq. of 4-(1H-tetrazol-5-yl)anilinewere reacted according to General Method 1. Yield: 17 mg (22% of theory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIpos): m/z=446 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.78 (s, 1H), 8.08-7.94 (m, 4H),7.87-7.80 (m, 3H), 7.78 (dd, 1H), 6.67 (d, 1H), 6.58 (d, 1H), 5.59 (q,1H), 1.71 (d, 3H).

Example 22-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-{4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]phenyl}propanamide(racemate)

95 mg (purity 83%, 0.26 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 75 mg (0.31 mmol) of4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) werereacted according to General Method 1. Yield: 30 mg (purity 92%, 21% oftheory)

LC/MS [Method 1]: R_(t)=1.06 min; MS (ESIpos): m/z=513 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.17 (s, 1H), 10.75 (s, 1H), 8.04(d, 1H), 8.00 (d, 2H), 7.96 (d, 1H), 7.81 (m, 3H), 7.77 (dd, 1H), 6.67(d, 1H), 6.57 (dd, 1 h), 5.59 (q, 1H), 1.71 (d, 3H).

Example 32-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-{4-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]phenyl}propanamide(racemate)

90 mg (purity 93%, 0.28 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 80 mg (0.33 mmol) of4-[3-(methoxymethyl)-1H-1,2,4-triazol-5-yl]aniline monohydrochloridewere reacted according to General Method 1. Yield: 45 mg (33% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=489 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.62 (br. s, 1H), 8.04 (d, 1H),7.99-7.92 (m, 3H), 7.82 (d, 1H), 7.77 (dd, 1H), 7.73 (m, 2H), 6.67 (d,1H), 6.56 (dd, 1H), 5.60 (q, 1H), 1.70 (d, 3H).

Example 42-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-imidazol-2-yl)phenyl]propanamide(racemate)

71 mg (0.23 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 40 mg (0.25 mmol) of4-(1H-imidazol-2-yl)aniline (Example 1.2A) were reacted according toGeneral Method 1. Yield: 4 mg (4% of theory)

LC/MS [Method 1]: R_(t)=0.66 min; MS (ESIpos): m/z=444 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.39 (br. s, 1H), 10.56 (br. s, 1H),8.05 (d, 1H), 7.96 (d, 1H), 7.88 (d, 2H), 7.82 (d, 1H), 7.77 (dd, 1H),7.67 (d, 2H), 7.21 (br. s, 1H), 6.99 (br. s, 1H), 6.67 (d, 1H), 6.56(dd, 1H), 5.60 (q, 1H), 1.70 (d, 3H).

Example 52-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-imidazol-4-yl)phenyl]propanamide(racemate)

78 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 44 mg (0.28 mmol) of4-(1H-imidazol-4-yl)aniline were reacted according to General Method 1.Yield: 40 mg (36% of theory)

LC/MS [Method 1]: R_(t)=0.74 min; MS (ESIpos): m/z=444 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.13 (br. s, 1H), 10.45 (s, 1H),8.05 (d, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.74-7.66 (m,3H), 7.61 (d, 2H), 7.52 (br. s, 1H), 6.67 (d, 1H), 6.56 (dd, 1H), 5.61(q, 1H), 1.69 (d, 3H).

Example 62-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-{4-[2-(trifluoromethyl)-1H-imidazol-5-yl]phenyl}propanamide(racemate)

67 mg (0.22 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 49 mg (0.22 mmol) of4-[2-(trifluoromethyl)-1H-imidazol-5-yl]aniline (Example 1.3B) werereacted according to General Method 1. Yield: 26 mg (22% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=512 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.66 (br. s, 1H), 10.51 (s, 1H),8.05 (d, 1H), 7.96 (d, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.81-7.74 (m,3H), 7.65 (d, 2H), 6.67 (d, 1H), 6.56 (dd, 1H), 5.61 (q, 1H), 1.70 (d,3H).

Example 72-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)phenyl]propanamide(racemate)

110 mg (0.20 mmol) of tert-butyl5-[4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate) (Example 2.3A) were hydrolysed with TFA according to GeneralMethod 2. Yield: 24 mg (27% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=460 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.79 (br. s, 1H), 10.55 (s, 1H),9.57 (br. s, 1H), 8.04 (d, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.77 (dd,1H), 7.68-7.59 (m, 4H), 6.67 (d, 1H), 6.56 (dd, 1H), 5.84 (br. s, 1H),5.60 (q, 1H), 1.70 (d, 3H).

Example 82-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]propanamide(racemate)

120 mg (purity 93%, 0.37 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 1.2 eq. of3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one (Example 1.5A) were reactedaccording to General Method 1. Yield: 23 mg (13% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=462 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.88 (br. s, 1H), 10.81 (s, 1H),8.05 (d, 1H), 7.96 (d, 1H), 7.82 (d, 1H), 7.81-7.78 (m, 4H), 7.77 (dd,1H), 6.67 (s, 1H), 6.57 (d, 1H), 5.57 (q, 1H), 1.71 (d, 3H).

Example 94-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

43 mg (0.09 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 2.2C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 20 mg (purity 89%, 48% of theory)

LC/MS [Method 1]: R_(t)=0.88 min; MS (ESIpos): m/z=422 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.73 (br. s, 1H), 10.74 (s, 1H),8.04 (d, 1H), 7.95 (d, 1H), 7.91 (d, 2H), 7.82 (d, 1H), 7.76 (dd, 1H),7.72 (d, 2H), 6.66 (d, 1H), 6.56 (dd, 1H), 5.58 (q, 1H), 1.70 (s, 3H).

Example 104-({2-[4-(5-Chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

15 mg (0.03 mmol) of methyl4-({2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 2.8F) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 4 mg (purity 92%, 28% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=421 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.72 (br. s, 1H), 10.75 (s, 1H),7.91 (d, 2H), 7.86 (d, 1H), 7.73 (d, 2H), 7.65 (d, 1H), 7.58 (d, 1H),7.54 (dd, 1H), 6.60 (d, 1H), 6.53 (dd, 1H), 5.57 (q, 1H), 3.57 (s, 1H),1.68 (d, 3H).

Example 114-({2-[4-(2,5-Dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

83 mg (0.17 mmol) of tert-butyl4-({2-[4-(2,5-dichlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 2.9C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 21 mg (purity 88%, 23% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=431 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.70 (s, 1H), 7.92-7.84 (m, 3H),7.68 (d, 2H), 7.63 (d, 1H), 7.59-7.52 (m, 2H), 6.48 (d, 1H), 6.42 (dd,1H), 5.58 (q, 1H), 1.68 (d, 3H).

Example 124-({2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

96 mg (0.18 mmol) of tert-butyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 2.10C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 69 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=475 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.76 (s, 1H),7.91 (d, 2H), 7.87 (d, 1H), 7.79 (d, 1H), 7.73 (d, 2H), 7.53 (d, 1H),7.46 (dd, 1H), 6.43 (s, 1H), 6.38 (dd, 1H), 5.57 (q, 1H), 1.68 (d, 3H).

Example 134-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl]amino}benzoicacid (racemate)

104 mg (0.20 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 2.11C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 67 mg (73% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=465 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (br. s, 1H), 10.74 (s, 1H),7.93-7.84 (m, 4H), 7.78-7.70 (m, 3H), 7.60 (d, 1H), 6.38 (d, 1H), 6.33(dd, 1H), 5.57 (q, 1H), 1.68 (d, 3H).

Example 144-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzoicacid (racemate)

82 mg (0.17 mmol) of methyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzoate(racemate) (Example 2.4A) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 8 mg (purity 93%, 10% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIpos): m/z=440 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.05 (br. s, 1H), 10.93 (s, 1H),8.05 (d, 1H), 7.95 (d, 1H), 7.86 (t, 1H), 7.83 (d, 1H), 7.77 (dd, 1H),7.66 (d, 1H), 7.40 (d, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 5.53 (q, 1H),1.70 (d, 3H).

Example 152-Chloro-4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

100 mg (purity 94%, 0.20 mmol) of methyl2-chloro-4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 2.5A) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 8 mg (purity 93%, 10% of theory)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=456 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.14 (br. s, 1H), 10.83 (s, 1H),8.04 (d, 1H), 7.94 (d, 1H), 7.90 (d, 1H), 7.86 (d, 1H), 7.81 (d, 1H),7.76 (dd, 1H), 7.57 (dd, 1H), 6.67 (d, 1H), 6.56 (dd, 1H), 5.52 (q, 1H),1.70 (d, 3H).

Example 164-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methylbenzoicacid (racemate)

120 mg (0.27 mmol) of methyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methylbenzoate(racemate) (Example 2.6A) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 39 mg (purity 93%, 33% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=436 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.61 (br. s, 1H), 10.64 (s, 1H),8.05 (d, 1H), 7.94 (d, 1H), 7.86-7.81 (m, 2H), 7.76 (dd, 1H), 7.56-7.49(m, 2H), 6.66 (d, 1H), 6.56 (dd, 1H), 5.56 (q, 1H), 1.69 (d, 3H).

Example 172-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)propanamide(racemate)

75 mg (0.14 mmol) of tert-butyl6-({2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate) (Example 2.7A) were hydrolysed with TFA according to GeneralMethod 2. Yield: 37 mg (60% of theory)

LC/MS [Method 1]: R_(t)=0.79 min; MS (ESIpos): m/z=448 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.65 (s, 1H), 10.20 (s, 1H), 8.05(d, 1H), 7.96 (d, 1H), 7.82 (d, 1H), 7.77 (dd, 1H), 7.74 (s, 1H), 7.56(d, 1H), 7.13 (dd, 1H), 6.66 (d, 1H), 6.56 (dd, 1H), 5.58 (q, 1H), 1.70(d, 3H).

Example 18N-(1H-Benzimidazol-6-yl)-2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanamide(racemate)

65 mg (purity 83%, 0.18 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid(racemate) (Example 2.2B) and 26 mg (0.20 mmol) of1H-benzimidazole-6-amine were reacted according to General Method 1.Yield: 11 mg (15% of theory)

LC/MS [Method 1]: R_(t)=0.64 min; MS (ESIpos): m/z=418 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.39 (s, 1H), 10.46 (s, 1H), 8.15(s, 1H), 8.08-7.95 (m, 3H), 7.83 (d, 1H), 7.77 (dd, 1H), 7.61-7.21 (m,2H), 6.68 (d, 1H), 6.57 (dd, 1H), 5.63 (m, 1H), 1.69 (d, 3H).

Example 192-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]butanamide(racemate)

212 mg (purity 60%, 0.4 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]butanoic acid(racemate) (Example 3.1C) and 31 mg (0.19 mmol) of4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1.Yield: 143 mg (77% of theory)

LC/MS [Method 1]: R_(t)=0.88 min; MS (ESIpos): m/z=460 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.77 (br. s, 1H), 10.87 (s, 1H),8.05 (d, 1H), 8.01 (d, 2H), 7.98 (d, 1H), 7.87-7.82 (m, 3H), 7.77 (dd,1H), 6.69 (d, 1H), 6.57 (dd, 1H), 5.62 (q, 1H), 2.25-2.15 (m, 1H),2.15-2.04 (m, 1H), 0.92 (t, 3H).

Example 202-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]butanamide(enantiomer 1)

Enantiomer separation of 140 mg of the racemate from Example 19 gave 51mg of the title compound Example 20 (enantiomer 1): Chiral HPLC:R_(t)=4.7 min; 99% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×20 mm; mobilephase A: isohexane, mobile phase B: ethanol+0.2% acetic acid; gradient:0.0 min 70% A→3 min 70% A→20 min 0% A→30 min 0% A; oven: 45° C.; flowrate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:90% isohexane, 10% ethanol; oven: 30° C.; flow rate: 1 ml/min; UVdetection: 220 nm.

Example 212-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]butanamide(enantiomer 2)

Enantiomer separation of 140 mg of the racemate from Example 19 gave 59mg of the title compound Example 21 (enantiomer 2): Chiral HPLC:R_(t)=10.7 min; 99% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×20 mm; mobilephase A: isohexane, mobile phase B: ethanol+0.2% acetic acid; gradient:0.0 min 70% A→3 min 70% A→20 min 0% A→30 min 0% A; oven: 45° C.; flowrate: 15 ml/min; UV detection: 220 nm; sample preparation: 140 mg ofracemate dissolved in 0.5 ml of triethanolamine/5.5 ml of ethanol.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:90% isohexane, 10% ethanol; oven: 30° C.; flow rate: 1 ml/min; UVdetection: 220 nm.

Example 222-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methyl-N-[4-(1H-tetrazol-5-yl)phenyl]butanamide(racemate)

79 mg (purity 86%, 0.21 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoicacid (racemate) (Example 4.1C) and 40 mg (0.25 mmol) of4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1.Yield: 45 mg (46% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=474 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.03 (s, 1H), 8.10 (d, 1H), 8.04 (d,3H), 8.01 (d, 2H), 7.87 (d, 2H), 7.84 (d, 1H), 7.76 (dd, 1H), 6.70 (d,1H), 6.57 (dd, 1H), 5.52 (d, 1H), 1.10 (d, 3H), 0.82 (d, 3H).

Example 232-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]hexanamide(racemate)

95 mg (purity 78%, 0.22 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]hexanoic acid(racemate) (Example 5.1C) and 42 mg (0.26 mmol) of4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1.Yield: 32 mg (30% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=488 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=16.77 (br. s, 1H), 10.88 (s, 1H),8.05 (d, 1H), 8.03-7.97 (m, 2H), 7.87-7.82 (m, 3H), 7.77 (dd, 1H), 6.68(d, 1H), 6.56 (dd, 1H), 5.71 (dd, 1H), 2.21-2.04 (m, 2H), 1.41-1.31 (m,2H), 1.29-1.20 (m, 2H), 0.88 (t, 3H).

Example 244-[(2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)-amino]benzoicacid (racemate)

200 mg (purity 48%, 0.19 mmol) of methyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate(racemate) (Example 6.1G) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 46 mg (49% of theory)

LC/MS [Method 1]: R_(t)=1.14 min; MS (ESIpos): m/z=505 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.84 (s, 1H),7.90 (t, 4H), 7.78-7.71 (m, 3H), 7.64 (d, 1H), 6.39 (d, 1H), 6.33 (dd,1H), 5.88-5.77 (m, 1H), 5.74-5.67 (m, 1H), 5.05-4.96 (m, 2H), 2.27-2.15(m, 2H), 2.11-1.93 (m, 2H).

Example 254-[(2-{4-[5-Chloro-2-(trifluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)-amino]benzoicacid (racemate)

77 mg (purity 92%, 0.12 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate(racemate) (Example 6.2C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 41 mg (64% of theory)

LC/MS [Method 3]: R_(t)=2.60 min; MS (ESIpos): m/z=521 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.84 (s, 1H),7.94-7.88 (m, 3H), 7.76-7.71 (m, 3H), 7.67 (dd, 1H), 6.58 (dd, 1H), 6.55(d, 1H), 6.45 (dd, 1H), 5.87-5.76 (m, 1H), 5.72-5.65 (m, 1H), 5.03-4.95(m, 2H), 2.27-2.17 (m, 2H), 2.09-1.92 (m, 2H).

Example 262-[4-(5-Chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenyl-N-[4-(1H-tetrazol-5-yl)phenyl]propanamide/diethylamineadduct (racemate)

77 mg (purity 85%, 0.17 mmol) of2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-phenylpropanoicacid (racemate) (Example 7.1C) and 31 mg (0.19 mmol) of4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1.Yield: 17 mg (purity 94%, 16% of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=522 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.66 (s, 1H), 8.16 (d, 1H), 8.01 (d,1H), 7.92 (d, 2H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 2H), 7.33-7.24(m, 4H), 7.21-7.16 (m, 1H), 6.56 (d, 1H), 6.50 (dd, 1H), 6.10 (dd, 1H),2.93 (q, 4H), 1.15 (t, 6H).

Example 274-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoyl]amino}benzoicacid (racemate)

163 mg (purity 93%, 0.25 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate(racemate) (Example 8.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 98 mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=542 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.92 (s, 1H),8.48 (d, 1H), 7.95-7.89 (m, 3H), 7.86 (d, 1H), 7.78-7.69 (m, 4H), 7.54(d, 1H), 7.35 (d, 1H), 7.25 (dd, 1H), 6.28 (d, 1H), 6.23-6.16 (m, 2H),3.71-3.56 (m, 2H).

Example 284-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoyl]amino}benzoicacid (racemate)

33 mg (purity 94%, 0.05 mmol) of tert-butyl4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-3-yl)propanoyl]amino}benzoate(racemate) (Example 9.1C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 11 mg (40% of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIpos): m/z=542 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (br. s, 1H), 10.87 (s, 1H),8.48 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.93 (d, 2H), 7.86 (d, 1H),7.76-7.71 (m, 3H), 7.61 (d, 1H), 7.54 (s, 1H), 7.28 (dd, 1H), 6.30.6.26(m, 2H), 6.05 (dd, 1H), 3.56-3.43 (m, 2H).

Example 294-({2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoyl}amino)benzoicacid (racemate)

65 mg (purity 85%, 0.10 mmol) of methyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-3-yl)propanoyl}amino)benzoate(racemate) (Example 9.2E) were hydrolysed with lithium hydroxideaccording to General Method 3. Yield: 14 mg (26% of theory)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=552 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (br. s, 1H), 10.86 (s, 1H),8.48 (s, 1H), 8.40 (d, 1H), 8.06 (d, 1H), 7.93 (d, 2H), 7.78-7.70 (m,3H), 7.65 (dd, 1H), 7.45 (d, 1H), 7.44 (dd, 1H), 7.31 (dd, 1H),6.35-6.31 (m, 2H), 6.05 (dd, 1H), 3.56-3.43 (m, 2H).

Example 304-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoicacid (racemate)

383 mg (0.62 mmol) of tert-butyl4-{[2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoate(racemate) (Example 10.1C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 180 mg (53% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=542 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.85 (br. s, 1H), 10.88 (s, 1H),8.64 (d, 2H), 8.01 (d, 1H), 7.94 (d, 2H), 7.87 (d, 1H), 7.77-7.70 (m,3H), 7.58-7.52 (m, 3H), 6.31-6.26 (m, 2H), 6.13 (dd, 1H), 3.72-3.59 (m,2H).

Example 314-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoicacid (enantiomer 1)

Enantiomer separation of 155 mg of the racemate from Example 30 gave 56mg (purity 89%) of the title compound Example 31 (enantiomer 1): ChiralHPLC: R_(t)=6.8 min; 100% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×20 mm; mobilephase: 50% isohexane, 46% ethanol, 4% 2% strength trifluoroacetic acidin ethanol; oven: 25° C.; flow rate: 20 ml/min; UV detection: 230 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 30° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 324-{[2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoyl]amino}benzoicacid (enantiomer 2)

Enantiomer separation of 155 mg of the racemate from Example 30 gave 21mg of the title compound Example 32 (enantiomer 2): Chiral HPLC:R_(t)=10.6 min; 95% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×20 mm; mobilephase: 50% isohexane, 46% ethanol, 4% 2% strength trifluoroacetic acidin ethanol; oven: 25° C.; flow rate: 20 ml/min; UV detection: 230 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 30° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 334-({2-[4-(2-Bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)benzoicacid (racemate)

734 mg (purity 92%, 1.11 mmol) of tert-butyl4-({2-[4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]-3-(pyridin-4-yl)propanoyl}amino)benzoate(racemate) (Example 10.2C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 126 mg (21% of theory)

LC/MS [Method 1]: R_(t)=0.83 min; MS (ESIpos): m/z=552 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.85 (br. s, 1H), 10.88 (s, 1H),8.48 (d, 2H), 8.02 (d, 1H), 7.93 (d, 2H), 7.78-7.71 (m 3H), 7.48 (d,1H), 7.44 (dd, 1H), 7.31 (d, 1H), 6.34 (d, 1H), 6.31 (dd, 1H), 6.09 (dd,1H), 3.57-3.49 (m, 2H).

Example 344-({2-[4-(5-Chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

53 mg (0.11 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 11.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 36 mg (77% of theory).

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=440 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.77 (s, 1H),8.24 (d, 1H), 8.09 (d, 1H), 7.91 (d, 2H), 7.88 (d, 1H), 7.82 (dd, 1H),7.72 (d, 2H), 6.67 (d, 1H), 5.55 (q, 1H), 1.72 (d, 3H).

Example 354-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

281 mg (purity 58%, 0.32 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 12.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 97 mg (67% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=456 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.77 (s, 1H), 8.19(s, 1H), 8.08 (d, 1H), 7.92 (d, 2H), 7.80 (d, 2H), 7.73 (d, 2H), 6.68(s, 1H), 5.56 (q, 1H), 1.74 (d, 3H).

Example 364-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 59 mg of the racemate from Example 35 gave 24mg of the title compound Example 36 (enantiomer 1): Chiral HPLC:R_(t)=8.6 min; 100% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×30 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 25° C.; flow rate: 40 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 30° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 374-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 59 mg of the racemate from Example 35 gave 15mg of the title compound Example 37 (enantiomer 2): Chiral HPLC:R_(t)=15.5 min; 100% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×30 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 25° C.; flow rate: 40 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 30° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 384-[(2-{5-Chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

79 mg (0.15 mmol) of tert-butyl4-[(2-{5-chloro-4-[5-chloro-2-(difluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 14.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 54 mg (76% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=481 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (br. s, 1H), 10.75/10.72 (2s,1H), 8.14/8.12 (2s, 1H), 7.92 (d, 2H), 7.80-7.70 (m, 4H), 7.54 (br. d,1H), 7.02-6.75 (br. t, 1H), 6.50/6.49 (2s, 1H), 5.57 (q, 1H), 1.73/1.71(2d, 3H).

Example 394-[(2-{5-Chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

75 mg (0.14 mmol) of tert-butyl4-[(2-{5-chloro-4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 15.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 56 mg (83% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=499 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.78/10.75 (2s, 1H),8.12/8.11 (2s, 1H), 7.95-7.89 (m, 3H), 7.80 (s, 1H), 7.72 (d, 2H), 7.69(br. t, 1H), 6.52/6.50 (2s, 1H), 5.57 (q, 1H), 1.73/1.71 (2d, 3H).

Example 404-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)-2-fluorobenzoicacid (racemate)

Under argon and at RT, 37 mg (0.30 mmol, 1.0 eq.) ofN,N′-diisopropylcarbodiimide were added to a solution of 100 mg (0.30mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) (Example 12.1D) in 2 ml of dichloroethane, the mixturewas stirred for 10 min, 46 mg (0.30 mmol) of 4-amino-2-fluorobenzoicacid were added and the mixture was stirred under reflux overnight.Subsequently, the reaction mixture was concentrated under reducedpressure and the crude product was purified by preparative HPLC(Reprosil C18, water/methanol gradient). Yield: 41 mg (29% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=474 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.04 (br. s, 1H), 10.93 (s, 1H),8.19 (s, 1H), 8.07 (d, 1H), 7.87 (t, 1H), 7.83-7.76 (m, 1H), 7.80 (dd,1H), 7.65 (dd, 1H), 7.41 (dd, 1H), 6.69 (s, 1H), 5.52 (q, 1H), 1.75 (d,3H).

Example 412-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-{4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]phenyl}propanamide(racemate)

126 mg (purity 66%, 0.25 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) (Example 12.1D) and 64 mg (0.27 mmol) of4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) werereacted according to General Method 1. Yield: 76 mg (57% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=547 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.20 (s, 1H), 10.77 (s, 1H), 8.20(s, 1H), 8.08 (d, 1H), 8.01 (d, 2H), 7.84-7.77 (m, 4H), 6.69 (s, 1H),5.58 (q, 1H), 1.76 (d, 3H).

Example 422-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)phenyl]propanamide(racemate)

17.8 mg (purity 78%, 0.02 mmol) of tert-butyl5-[4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate) (Example 12.2A) were reacted with TFA according to GeneralMethod 2. Yield: 6 mg (55% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIpos): m/z=494 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.96 (br. s, 1H), 10.54 (s, 1H),9.56 (br. s, 1H), 8.18 (s, 1H), 8.07 (d, 1H), 7.80 (m, 2H), 7.63 (m,4H), 6.67 (s, 1H), 5.85 (br. s, 1H), 5.59 (q, 1H), 1.73 (d, 3H).

Example 432-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[4-(1H-imidazol-4-yl)phenyl]propanamide(racemate)

102 mg (purity 82%, 0.25 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) (Example 12.1D) and 43 mg (0.27 mmol) of4-0H-imidazol-4-yl)aniline were reacted according to General Method 1.Yield: 5 mg (purity 94%, 4% of theory)

LC/MS [Method 1]: R_(t)=0.75 min; MS (ESIpos): m/z=478 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.22 (br. s, 1H), 10.46 (s, 1H),8.20 (s, 1H), 8.08 (d, 1H), 7.82 (m, 2H), 7.73 (m, 3H), 7.61 (d, 2H),7.53 (br. s, 1H), 6.69 (s, 1H), 5.62 (q, 1H), 1.75 (d, 3H).

Example 442-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-N-[2-(trifluoromethyl)-1H-benzimidazol-6-yl]propanamide(racemate)

68 mg (purity 94%, 0.20 mmol) of2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoicacid (racemate) (Example 12.1D) and 44 mg (0.22 mmol) of2-(trifluoromethyl)-1H-benzimidazole-6-amine were reacted according toGeneral Method 1. Yield: 63 mg (60% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=520 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.85 (s, 1H), 10.64 (s, 1H), 8.22(s, 1H), 8.18 (s, 1H), 8.08 (d, 1H), 7.80 (m, 2H), 7.74 (br. s, 1H),7.41 (br. s, 1H), 6.69 (s, 1H), 1.06 (q, 1H), 1.76 (d, 3H).

Example 454-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoicacid (racemate)

192 mg (0.34 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate(racemate) (Example 13.1D) were hydrolysed with TFA according to GeneralMethod 2. Yield: 141 mg (82% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=496 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.80 (s, 1H), 10.83 (s, 1H), 8.25(s, 1H), 8.07 (d, 1H), 7.92 (d, 2H), 7.84-7.78 (m, 2H), 7.73 (d, 2H),6.69 (s, 1H), 5.76 (m, 1H), 2.25 (m, 1H), 1.91 (m, 1H), 0.70-0.60 (m,1H), 0.48-0.32 (m, 2H), 0.22-0.09 (m, 2H).

Example 464-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 138 mg of the racemate from Example 45 gave 42mg of the title compound Example 46 (enantiomer 1): Chiral HPLC:R_(t)=5.7 min; 100% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×30 mm; mobilephase: 50% isohexane, 50% 2-propanol; oven: 20° C.; flow rate: 50ml/min; UV detection: 270 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% 2-propanol+0.2% TFA in 1% water; oven: 20° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 474-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 138 mg of the racemate from Example 45 gave 41mg of the title compound Example 47 (enantiomer 2): Chiral HPLC:R_(t)=11.9 min; 97% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250×30 mm; mobilephase: 50% isohexane, 50% 2-propanol; oven: 20° C.; flow rate: 50ml/min; UV detection: 270 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% 2-propanol+0.2% TFA in 1% water; oven: 20° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 484-({2-[4-(5-Chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

93 mg (0.19 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 16.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 91 mg (quant.)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=447 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.80 (br. s, 1H), 10.83 (s, 1H),8.87 (s, 1H), 8.13 (d, 1H), 7.95-7.89 (m, 3H), 7.86 (dd, 1H), 7.72 (d,2H), 6.78 (s, 1H), 5.57 (q, 1H), 1.78 (d, 3H).

Example 494-[(2-{4-[5-Chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

48 mg (0.09 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 17.1D) were hydrolysed with TFA according to GeneralMethod 2. Yield: 30 mg (70% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=472 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.80 (s, 1H), 10.80 (s, 1H), 8.79(s, 1H), 7.92 (d, 2H), 7.84-7.58 (m, 5H), 7.12-6.85 (br. t, 1H), 6.54(s, 1H), 5.58 (q, 1H), 1.75 (d, 3H).

Example 504-[(2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

124 mg (0.22 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 18.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 85 mg (79% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=490 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.82 (d, 1H), 8.79(s, 1H), 7.96 (dd, 1H), 7.92 (d, 2H), 7.87-7.69 (m, 4H), 6.85 (s, 1H),5.57 (q, 1H), 1.76 (d, 3H).

Example 514-[(2-{4-[5-Chloro-2-(trifluoromethoxy)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

107 mg (purity 94%, 0.18 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-cyano-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) (Example 18.2A) were hydrolysed with TFA according to GeneralMethod 2. Yield: 59 mg (65% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=506 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.80 (s, 1H), 8.79(s, 1H), 7.92 (d, 2H), 7.78-7.61 (m, 5H), 6.65 (s, 1H), 5.55 (q, 1H),1.76 (d, 3H).

Example 524-({2-[4-(5-Chloro-2-cyclopropylphenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

66 mg (0.13 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate) (Example 18.3A) were hydrolysed with TFA according toGeneral Method 2. Yield: 39 mg (68% of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=462 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.79 (s, 1H), 8.76(s, 1H), 7.92 (d, 2H), 7.71 (d, 2H), 7.45 (dd, 1H), 7.34 (s, 1H), 7.06(d, 1H), 6.54 (s, 1H), 5.57 (q, 1H), 1.76 (d, 3H), 1.70 (m, 1H), 0.93(d, 2H), 0.74 (d, 2H).

Example 534-({2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

64 mg (0.12 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethyl)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 19.1F) were hydrolysed with TFA according to GeneralMethod 2. Yield: 46 mg (80% of theory)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIpos): m/z=472 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.83 (s, 1H), 8.30(s, 1H), 8.02 (d, 1H), 7.91 (d, 2H), 7.79-7.69 (m, 4H), 6.85 (br. t,1H), 6.57 (s, 1H), 5.58 (q, 1H), 1.74 (d, 3H).

Example 544-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

251 mg (purity 79%, 0.36 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 20.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 35 mg (20% of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=490 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.80 (s, 1H), 10.80 (d, 1H), 8.33(d, 1H), 8.06 (dd, 1H), 7.92 (d, 2H), 7.85-7.68 (m, 4H), 6.68 (d, 1H),5.63 (q, 1H), 1.79 (t, 3H).

Example 554-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

42 mg (0.08 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 21.1E) were hydrolysed with TFA according to GeneralMethod 2. Yield: 24 mg (64% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIpos): m/z=452 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.71 (s, 1H), 8.01(d, 1H), 7.91 (d, 2H), 7.77-7.71 (m, 4H), 7.47 (s, 1H), 6.53 (s, 1H),5.60 (q, 1H), 3.70 (s, 3H), 1.74 (d, 3H).

Example 564-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 430 mg of the racemate from Example 55 gave 214mg of the title compound Example 56 (enantiomer 1): Chiral HPLC:R_(t)=4.3 min; 99% ee.

Separation method: column: Daicel Chiralpak OZ 5 μm 250×20 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 40° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak OZ 5 μm 250×4.6 mm; mobile phase: 30%isohexane, 70% ethanol+0.2% TFA in 1% water; oven: 45° C.; flow rate: 1ml/min; UV detection: 220 nm.

Example 574-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 430 mg of the racemate from Example 55 gave 223mg of the title compound Example 57 (enantiomer 2): Chiral HPLC:R_(t)=5.9 min; 99% ee.

Separation method: column: Daicel Chiralpak OZ 5 μm 250×20 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 40° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak OZ 5 μm 250×4.6 mm; mobile phase: 30%isohexane, 70% ethanol+0.2% TFA in 1% water; oven: 45° C.; flow rate: 1ml/min; UV detection: 220 nm.

Example 584-({2-[4-(5-Chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

32 mg (0.06 mmol) of tert-butyl4-({2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 21.2D) were hydrolysed with TFA according to GeneralMethod 2. Yield: 10 mg (36% of theory)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=472 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.69 (s, 1H),8.14 (d, 1H), 7.91 (d, 2H), 7.80 (dd, 1H), 7.77-7.70 (m, 3H), 7.34 (s,1H), 6.59 (s, 1H), 5.59 (q, 1H), 3.55 (s, 3H), 1.71 (d, 3H).

Example 594-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoicacid (enantiomer 1)

161 mg (0.29 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate(racemate) (Example 22.1D) were hydrolysed with TFA according to GeneralMethod 2.

Subsequent enantiomer separation of 88 mg of the racemate gave 56 mg ofthe title compound Example 59 (enantiomer 1): Chiral HPLC: R_(t)=4.1min; 99% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250×20 mm; mobilephase: 25% isohexane, 75% ethanol; oven: 45° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak IF 5 μm 250×4.6 mm; mobile phase: 25%isohexane, 75% ethanol+0.2% TFA in 1% water; oven: 30° C.; flow rate: 1ml/min; UV detection: 220 nm.

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=492 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.79 (s, 1H),8.00 (d, 1H), 7.91 (d, 2H), 7.78-7.71 (m, 4H), 7.54 (s, 1H), 6.53 (s,1H), 5.80 (dd, 1H), 3.70 (s, 3H), 2.28-2.18 (m, 1H), 1.96-1.87 (m, 1H),0.71-0.61 (m, 1H), 0.47-0.33 (m, 2H), 0.23-0.10 (m, 2H).

Example 604-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoicacid (enantiomer 2)

150 mg (0.27 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclopropylpropanoyl}amino)benzoate(Example 22.1D) were hydrolysed with TFA according to General Method 2.

Subsequent enantiomer separation of 81 mg of the racemate gave 52 mg ofthe title compound Example 60 (enantiomer 2): Chiral HPLC: R_(t)=5.4min; 98% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250×20 mm; mobilephase: 25% isohexane, 75% ethanol; oven: 45° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak IF 5 μm 250×4.6 mm; mobile phase: 25%isohexane, 75% ethanol+0.2% TFA in 1% water; oven: 30° C.; flow rate: 1ml/min; UV detection: 220 nm.

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIpos): m/z=492 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.79 (s, 1H),8.00 (d, 1H), 7.91 (d, 2H), 7.78-7.71 (m, 4H), 7.54 (s, 1H), 6.53 (s,1H), 5.80 (dd, 1H), 3.70 (s, 3H), 2.28-2.18 (m, 1H), 1.96-1.87 (m, 1H),0.71-0.61 (m, 1H), 0.47-0.33 (m, 2H), 0.23-0.10 (m, 2H).

Example 614-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoyl}amino)benzoicacid (racemate)

91 mg (0.17 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]pent-4-ynoyl}amino)benzoate(racemate) (Example 23.1C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 55 mg (67% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=476 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.78 (s, 1H), 8.01(d, 1H), 7.92 (d, 2H), 7.78-7.71 (m, 4H), 7.60 (s, 1H), 6.55 (s, 1H),5.78 (dd, 1H), 3.69 (s, 3H), 3.30-3.22 (m, 1H), 3.18-3.10 (m, 1H),3.01-2.97 (m, 1H).

Example 624-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

31 mg (0.06 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(propan-2-yloxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) (Example 24.11) were hydrolysed with TFA according to GeneralMethod 2. Yield: 5 mg (18% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=480 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.73 (s, 1H), 8.01(d, 1H), 7.92 (d, 2H), 7.77-7.70 (m, 4H), 7.55 (s, 1H), 6.53 (s, 1H),5.65 (q, 1H), 4.10-4.02 (m, 1H), 1.71 (d, 3H), 1.07 (dd, 6H).

Example 634-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoicacid (racemate)

127 mg (0.23 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate(racemate) (Example 25.1C) were hydrolysed with TFA according to GeneralMethod 2. Yield: 79 mg (71% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=494 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.85 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H),5.86 (dd, 1H), 3.69 (s, 3H), 2.27-2.17 (br. m, 1H), 1.93-1.84 (br. m,1H), 1.49-1.39 (br. m, 1H), 0.95 (t, 6H).

Example 644-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 73 mg of the racemate from Example 63 gave 37mg of the title compound Example 64 (enantiomer 1): Chiral HPLC:R_(t)=4.6 min; 99% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250×20 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 40° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 40° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 654-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 73 mg of the racemate from Example 63 gave 33mg of the title compound Example 65 (enantiomer 2): Chiral HPLC:R_(t)=7.0 min; 99% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250×20 mm; mobilephase: 50% isohexane, 50% ethanol; oven: 40° C.; flow rate: 15 ml/min;UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250×4.6 mm; mobile phase:50% isohexane, 50% ethanol+0.2% TFA in 1% water; oven: 40° C.; flowrate: 1 ml/min; UV detection: 220 nm.

Example 664-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoicacid (racemate)

68 mg (0.13 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate(racemate) (Example 26.1B) were hydrolysed with TFA according to GeneralMethod 2. Yield: 51 mg (84% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=466 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.81 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H),5.64 (dd, 1H), 3.69 (s, 3H), 2.25-2.11 (m, 2H), 0.91 (t, 3H).

Alternative Synthesis:

At RT, 0.2 ml of water and 97 mg (1.22 mmol, 3.0 eq.) of sodiumhydroxide were added to a suspension of 200 mg (0.41 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate(racemate) in 2.0 ml of ethanol. The reaction mixture was stirred at RTfor 1 h and at an oil bath temperature of 60° C. for 6 h, allowed tostand at RT overnight and then added to aqueous hydrochloric acid (1N).After dilution with water a precipitate was formed which was filteredoff, washed twice with water and dried under reduced pressure. Theprecipitate was then purified by flash chromatography (25 g of silicagel, mobile phase: dichloromethane→dichloromethane/methanol 50:1).Yield: 144 mg (38% of theory based on 0.82 mmol, since two crude productbatches of the stated size were purified together)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIneg): m/z=464 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.74 (s, 1H), 10.80 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.70 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H),5.65 (dd, 1H), 3.69 (s, 3H), 2.26-2.11 (m, 2H), 0.91 (t, 3H).

Example 674-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 433 mg of the racemate from Example 66 gave 196mg of the title compound Example 67 (enantiomer 1): Chiral HPLC:R_(t)=5.22 min; 99% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250 mm×20 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% acetic acid; temperature: 40° C.;flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 40°C.; flow rate: 1 ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.81 (s, 1H), 8.00(d, 1H), 7.91 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H),5.64 (dd, 1H), 3.69 (s, 3H), 2.26-2.11 (m, 2H), 0.91 (t, 3H).

Example 684-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 433 mg of the racemate from Example 66 gave 201mg of the title compound Example 68 (enantiomer 2): Chiral HPLC:R_(t)=8.19 min; 99% ee.

Separation method: column: Daicel Chiralpak IF 5 μm 250 mm×20 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% acetic acid; temperature: 40° C.;flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 40°C.; flow rate: 1 ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.81 (s, 1H), 8.00(d, 1H), 7.91 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H),5.64 (dd, 1H), 3.69 (s, 3H), 2.26-2.11 (m, 2H), 0.91 (t, 3H).

Example 692-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-2,5-dihydro-1H-pyrazol-3-yl)phenyl]butanamide(racemate)

17 mg (purity 70%, 0.02 mmol) of tert-butyl5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 8 mg (78% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=504 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.96 (br. s, 1H), 10.57 (s, 1H),9.54 (br. s, 1H), 8.00 (d, 1H), 7.74 (s, 1H), 7.73 (d, 1H), 7.66 (d,2H), 7.61 (d, 2H), 7.51 (s, 1H), 6.54 (s, 1H), 5.84 (br. s, 1H), 5.64(dd, 1H), 3.69 (s, 3H), 2.24-2.10 (m, 2H), 0.91 (t, 3H).

Example 702-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)butanamide(racemate)

112 mg (0.19 mmol) of tert-butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 34 mg (35% of theory)

LC/MS [Method 1]: R_(t)=0.85 min; MS (ESIpos): m/z=492 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.73 (s, 1H), 10.21 (s, 1H), 8.00(d, 1H), 7.81-7.71 (m, 3H), 7.57 (d, 1H), 7.51 (s, 1H), 7.16 (dd, 1H),6.55 (s, 1H), 5.65 (dd, 1H), 3.69 (s, 3H), 2.27-2.10 (m, 2H), 0.91 (t,3H).

Example 712-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanamide(racemate)

71 mg (0.20 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 33 mg (0.22 mmol, 1.1 eq.) of5-amino-1,3-dihydro-2H-benzimidazol-2-one were reacted according toGeneral Method 1. Yield: 74 mg (76% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=478 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.58 (s, 1H), 10.53 (s, 1H), 10.37(s, 1H), 8.00 (d, 1H), 7.77-7.70 (m, 2H), 7.53 (s, 1H), 7.45 (d, 1H),7.08 (dd, 1H), 6.85 (d, 1H), 6.53 (s, 1H), 5.63 (dd, 1H), 3.69 (s, 3H),2.22-2.03 (m, 2H), 0.90 (t, 3H).

Example 722-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(2-oxo-2,3-dihydro-1,3-oxazol-5-yl)phenyl]butanamide(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 60 mg (0.30 mmol, 1.2 eq.) of5-(4-aminophenyl)-1,3-oxazol-2(3H)-one were reacted according to GeneralMethod 1. Yield: 23 mg (purity 93%, 17% of theory)

LC/MS [Method 8]: R_(t)=1.16 min; MS (ESIneg): m/z=503 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.77 (s, 1H), 10.60 (s, 1H), 8.00(d, 1H), 7.76-7.70 (m, 2H), 7.67 (d, 2H), 7.50 (s, 1H), 7.46 (d, 2H),7.39 (d, 1H), 6.53 (s, 1H), 5.63 (dd, 1H), 3.69 (s, 3H), 2.25-2.09 (m,2H), 0.90 (t, 3H).

Example 736-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-benzimidazole-2-carboxylicacid (racemate)

86 mg (0.16 mmol) of ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-benzimidazole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 3. Yield: 67 mg (82% of theory)

LC/MS [Method 1]: R_(t)=0.76 min; MS (ESIpos): m/z=506 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.68 (s, 1H), 8.17 (s, 1H), 8.01 (d,1H), 7.78-7.71 (m, 2H), 7.64 (d, 1H), 7.54 (s, 1H), 7.46 (dd, 1H), 6.55(s, 1H), 5.66 (dd, 1H), 3.70 (s, 3H), 2.28-2.10 (m, 2H), 0.91 (t, 3H).

Example 746-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylicacid (racemate)

75 mg (0.14 mmol) of ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 3. Yield: 38 mg (48% of theory)

LC/MS [Method 1]: R_(t)=1.18 min; MS (ESIneg): m/z=503 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.84 (br. s, 1H), 11.70 (s, 1H),10.55 (s, 1H), 8.06-7.98 (m, 2H), 7.79-7.70 (m, 2H), 7.57 (d, 1H), 7.54(s, 1H), 7.19 (dd, 1H), 7.03 (s, 1H), 6.54 (s, 1H), 5.68 (dd, 1H), 3.70(s, 3H), 2.27-2.08 (m, 2H), 0.92 (t, 3H).

Example 755-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylicacid (racemate)

94 mg (0.18 mmol) of ethyl5-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-1H-indole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 3. Yield: 39 mg (43% of theory)

LC/MS [Method 1]: R_(t)=1.15 min; MS (ESIneg): m/z=503 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.77 (s, 1H), 10.26 (s, 1H), 8.00(d, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.73 (dd, 1H), 7.56 (s, 1H), 7.22(d, 1H), 7.15 (d, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 5.68 (dd, 1H), 3.70(s, 3H), 2.25-2.02 (m, 2H), 0.90 (t, 3H).

Example 764-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoicacid (racemate)

1.80 g (3.40 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate(racemate) in 45 ml of methanol/water (4/1) were reacted with 2.24 g(6.87 mmol) of caesium carbonate according to General Method 4, givingthe title compound. Yield: 1.66 g (88% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIneg): m/z=494 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.91 (d, 2H), 7.77 (d, 2H), 7.75 (s, 1H), 7.74 (dd, 1H), 7.51 (s,1H), 6.53 (s, 1H), 5.76 (t, 1H), 3.69 (s, 3H), 3.43-3.25 (m, 2H), 3.20(s, 3H), 2.44-2.39 (m, 2H).

Example 77(+)-4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 1.66 g of the racemate from Example 76 gave 707mg of the title compound Example 77 (enantiomer 1): Chiral HPLC:R_(t)=4.59 min; 99% ee.

Optical rotation: [α]₅₈₉ ^(20.1)=+95.82° (c 0.255 g/100 ml, methanol)

Separation method (SFC): column: AZ-H 5 μm 250 mm×20 mm; mobile phase:70% carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 3 ml/min;pressure: 100 bar; UV detection: 210 nm.

Example 78(−)-4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 1.66 g of the racemate from Example 76 gave 631mg of the title compound Example 78 (enantiomer 2): Chiral HPLC:R_(t)=8.11 min; 98% ee.

Optical rotation: [α]₅₈₉ ^(19.9)=−95.05° (c 0.33 g/100 ml, methanol)

Separation method (SFC): column: AZ-H 5 μm 250×20 mm; mobile phase: 70%carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 80 ml/min;pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250×4.6 mm; mobile phase: 70% carbondioxide, 30% ethanol; temperature: 40° C.; flow rate: 3 ml/min;pressure: 100 bar; UV detection: 210 nm.

Example 794-({(4S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

387 mg (0.66 mmol) of tert-butyl4-({(4S)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. Yield: 245 mg (70% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=510 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.80/10.75 (2×s,1H), 8.00 (d, 1H), 7.94-7.87 (m, 2H), 7.81-7.71 (m, 4H), 7.57/7.51 (2×s,1H), 6.53 (2×s, 1H), 5.89-5.80 (m, 1H), 3.69 (s, 3H),3.25-3.19/3.17-3.09 (2×m, 1H), 3.19/3.12 (2×s, 3H), 2.43-2.28 (m, 1H),2.28-2.17 (m, 1H), 1.16/1.14 (2×d, 3H).

Example 804-({(4S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoicacid (enantiomerically pure diastereomer 1)

Diastereomer separation of 240 mg of the mixture from Example 79 gave 57mg of the title compound Example 80 (enantiomerically pure diastereomer1): Chiral HPLC: R_(t)=8.1 min; diastereomeric purity: >99%.

Separation method: column: Daicel Chiralpak IF 5 μm 250 mm×20 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 23°C.; flow rate: 20 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 40°C.; flow rate: 1 ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.75 (s, 1H), 8.00(d, 1H), 7.90 (d, 2H), 7.81-7.70 (m, 4H), 7.51 (s, 1H), 6.53 (s, 1H),5.84 (dd, 1H), 3.69 (s, 3H), 3.17-3.08 (m, 1H), 3.12 (s, 3H), 2.44-2.34(m, 1H), 2.29-2.18 (m, 1H), 1.14 (d, 3H).

Example 814-({(4S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoicacid (enantiomerically pure diastereomer 2)

Diastereomer separation of 240 mg of the mixture from Example 79 gave 10mg of the title compound Example 81 (enantiomerically pure diastereomer2): Chiral HPLC: R_(t)=10.9 min; diastereomeric purity: 98%.

Separation method: column: Daicel Chiralpak IF 5 μm 250 mm×20 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 23°C.; flow rate: 20 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; temperature: 40°C.; flow rate: 1 ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.75 (br. s, 1H), 10.77 (s, 1H),7.99 (d, 1H), 7.91 (d, 2H), 7.81-7.70 (m, 4H), 7.57 (s, 1H), 6.53 (s,1H), 5.85 (dd, 1H), 3.69 (s, 3H), 3.26-3.20 (m, 1H), 3.19 (s, 3H),2.36-2.27 (m, 1H), 2.26-2.18 (m, 1H), 1.16 (d, 3H).

Example 824-({(4R)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

51 mg (0.09 mmol) of tert-butyl4-({(4R)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. Yield: 27 mg (58% of theory)

LC/MS [Method 8]: R_(t)=1.20 min; MS (ESIneg): m/z=508 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (br. s, 1H), 10.80/10.74 (2×s,1H), 8.00 (d, 1H), 7.94-7.86 (m, 2H), 7.81-7.70 (m, 4H), 7.57/7.51 (2×s,1H), 6.53 (2×s, 1H), 5.89-5.79 (m, 1H), 3.69 (s, 3H),3.25-3.19/3.17-3.09 (2×m, 1H), 3.19/3.12 (2×s, 3H), 2.43-2.28 (m, 1H),2.28-2.17 (m, 1H), 1.16/1.14 (2×d, 3H).

Example 834-({(4R)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoic acid (enantiomerically purediastereomer 1)

26 mg (0.05 mmol) of tert-butyl4-({(4R)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxypentanoyl}amino)benzoate(enantiomerically pure diastereomer 1) were hydrolysed with TFAaccording to General Method 2. Yield: 11 mg (45% of theory)

LC/MS [Method 8]: R_(t)=1.20 min; MS (ESIneg): m/z=508 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (br. s, 1H), 10.74 (s, 1H),8.00 (d, 1H), 7.94-7.86 (m, 2H), 7.81-7.70 (m, 4H), 7.51 (s, 1H), 6.53(s, 1H), 5.84 (dd, 1H), 3.69 (s, 3H), 3.25-3.09 (m, 1H), 3.12 (s, 3H),2.43-2.28 (m, 1H), 2.28-2.17 (m, 1H), 1.14 (d, 3H).

Example 844-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

327 mg (0.57 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. Yield: 227 mg (purity 94%, 72%of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=522 (M+H)⁺.

Example 854-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 1)

Diastereomer separation of 227 mg of the mixture from Example 84 gave 61mg of the title compound Example 85 (enantiomerically pure diastereomer1): Chiral HPLC: R_(t)=4.04 min; diastereomeric purity: >99%.

Separation method (SFC): column: Daicel Chiralpak IF 5 μm 250 mm×20 mm;mobile phase: 80% carbon dioxide, 20% ethanol; temperature: 40° C.; flowrate: 100 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 60% carbon dioxide, 40% ethanol; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.80 (s, 1H), 8.00 (d, 1H), 7.91 (d,2H), 7.81-7.70 (m, 4H), 7.55 (s, 1H), 6.52 (s, 1H), 5.83 (t, 1H),3.80-3.70 (m, 2H), 3.68 (s, 3H), 3.59 (q, 1H), 2.39-2.24 (m, 2H),2.01-1.72 (3×m, 3H), 1.69-1.57 (m, 1H).

Example 864-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 2)

Diastereomer separation of 227 mg of the mixture from Example 84 gave 70mg of the title compound Example 86 (enantiomerically pure diastereomer2): Chiral HPLC: R_(t)=6.62 min; diastereomeric purity: 95%.

Separation method (SFC): column: Daicel Chiralpak IF 5 μm 250 mm×20 mm;mobile phase: 80% carbon dioxide, 20% ethanol; temperature: 40° C.; flowrate: 100 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 60% carbon dioxide, 40% ethanol; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.79 (s, 1H), 8.00 (d, 1H), 7.91 (d,2H), 7.81-7.70 (m, 4H), 7.51 (s, 1H), 6.52 (s, 1H), 5.81 (dd, 1H),3.81-3.73 (m, 1H), 3.73-3.65 (m, 1H), 3.69 (s, 3H), 3.63-3.54 (q, 1H),2.50-2.41 (m, 1H), 2.31-2.21 (m, 1H), 2.01-1.72 (3×m, 3H), 1.55-1.42 (m,1H).

Example 874-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

1612 mg (2.78 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. Yield: 1270 mg (purity 90%, 79%of theory)

LC/MS [Method 8]: R_(t)=1.19 min; MS (ESIpos): m/z=522 (M+H)⁺.

Example 884-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 1)

Diastereomer separation of 1270 mg of the mixture from Example 87 gave350 mg of the title compound Example 88 (enantiomerically purediastereomer 1): Chiral HPLC: R_(t)=4.31 min; diastereomeric purity:>99%.

Separation method (SFC): column: Daicel Chiralpak IC 5 μm 250 mm×20 mm;mobile phase: 25% carbon dioxide, 75% ethanol; temperature: 40° C.; flowrate: 100 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel IC 5 μm 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.75 (br. s, 1H), 10.77 (s, 1H),7.99 (d, 1H), 7.91 (d, 2H), 7.77 (d, 2H), 7.75-7.70 (m, 2H), 7.55 (s,1H), 6.52 (s, 1H), 5.83 (t, 1H), 3.80-3.70 (m, 2H), 3.68 (s, 3H), 3.59(q, 1H), 2.36-2.24 (m, 2H), 2.01-1.72 (3×m, 3H), 1.69-1.57 (m, 1H).

Example 894-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydrofuran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 2)

Diastereomer separation of 1270 mg of the mixture from Example 87 gave452 mg of the title compound Example 89 (enantiomerically purediastereomer 2): Chiral HPLC: R_(t)=6.69 min; diastereomeric purity:>99%.

Separation method (SFC): column: Daicel Chiralpak IC 5 μm 250 mm×20 mm;mobile phase: 25% carbon dioxide, 75% ethanol; temperature: 40° C.; flowrate: 100 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel IC 5 μm 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.74 (s, 1H), 10.77 (s, 1H), 7.99(d, 1H), 7.90 (d, 2H), 7.80-7.70 (m, 4H), 7.51 (s, 1H), 6.52 (s, 1H),5.81 (dd, 1H), 3.81-3.73 (m, 1H), 3.73-3.65 (m, 1H), 3.69 (s, 3H), 3.59(q, 1H), 2.50-2.41 (m, 1H), 2.31-2.22 (m, 1H), 2.01-1.72 (3×m, 3H),1.54-1.43 (m, 1H).

Example 904-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoicacid (mixture of racemic diastereomers)

795 mg (1.3 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 2. Yield: 405 mg (59% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIpos): m/z=522 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.86/10.85 (2×s, 1H),8.00 (d, 1H), 7.92 (d, 2H), 7.80-7.70 (m, 4H), 7.56/7.53 (2×s, 1H), 6.55(s, 1H), 5.81/5.76 (2×dd, 1H), 3.82-3.68 (m, 2H), 3.70 (s, 3H), 3.60 (q,1H), 3.44/3.26 (2×dd, 1H), 2.39-2.26 (m, 1H), 2.23-2.10 (m, 1H),2.05-1.88 (m, 2H), 1.74-1.62/1.58-1.45 (2×m, 1H).

Example 914-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoicacid (enantiomer 1 of the second diastereomer)

Diastereomer and enantiomer separation of 400 mg of the mixture fromExample 90 gave 8 mg of the title compound Example 91 (enantiomer 1 ofthe second diastereomer): Chiral HPLC: R_(t)=5.73 min; >99% ee.

Separation method (SFC): column: Daicel Chiralpak AD-H 5 μm 250 mm×20mm; mobile phase: 80% carbon dioxide, 20% ethanol; temperature: 40° C.;flow rate: 80 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 70% carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.74 (s, 1H), 10.84 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.82-7.68 (m, 4H), 7.53 (s, 1H), 6.55 (s, 1H),5.81 (br. s, 1H), 3.82-3.65 (m, 2H), 3.70 (s, 3H), 3.65-3.53 (m, 1H),3.30-3.23 (m, 1H), 2.39-2.26 (m, 1H), 2.23-2.10 (m, 1H), 2.07-1.88 (m,2H), 1.74-1.62 (m, 1H).

Example 924-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoicacid (enantiomer 2 of the second diastereomer)

Diastereomer and enantiomer separation of 400 mg of the mixture fromExample 90 gave 32 mg of the title compound Example 92 (enantiomer 2 ofthe second diastereomer): Chiral HPLC: R_(t)=8.96 min; >99% ee.

Separation method (SFC): column: Daicel Chiralpak OJ-H 5 μm 250 mm×20mm; mobile phase: 75% carbon dioxide, 25% ethanol; temperature: 40° C.;flow rate: 80 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 70% carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.74 (s, 1H), 10.83 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.70 (m, 4H), 7.53 (s, 1H), 6.55 (s, 1H),5.81 (dd, 1H), 3.80-3.72 (m, 2H), 3.70 (s, 3H), 3.60 (q, 1H), 3.28 (dd,1H), 2.38-2.28 (m, 1H), 2.21-2.11 (m, 1H), 2.06-1.89 (m, 2H), 1.73-1.63(m, 1H).

Example 934-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydrofuran-3-yl)propanoyl}amino)benzoicacid (enantiomer 2 of the first diastereomer)

Diastereomer and enantiomer separation of 400 mg of the mixture fromExample 90 gave 43 mg of the title compound Example 93 (enantiomer 2 ofthe first diastereomer): Chiral HPLC: R_(t)=10.27 min; >99% ee.

Separation method (SFC): column: Daicel Chiralpak OJ-H 5 μm 250 mm×20mm; mobile phase: 75% carbon dioxide, 25% ethanol; temperature: 40° C.;flow rate: 80 ml/min; UV detection: 210 nm.

Analysis (SFC): column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 70% carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.85 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.80-7.70 (m, 4H), 7.56 (s, 1H), 6.55 (s, 1H),5.77 (dd, 1H), 3.79-3.67 (m, 2H), 3.70 (s, 3H), 3.60 (q, 1H), 3.44 (dd,1H), 2.37-2.27 (m, 1H), 2.23-2.13 (m, 1H), 2.05-1.93 (m, 2H), 1.58-1.45(m, 1H).

Example 944-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoicacid (racemate)

1.07 g (1.89 mmol) of ethyl({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate(racemate) in 24 ml of methanol/water (4/1) were reacted with 1.24 g(3.79 mmol) of caesium carbonate according to General Method 4. Yield:1.24 g (purity 73%, 88% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIneg): m/z=534 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.92 (d, 2H), 7.78-7.72 (m, 4H), 7.52 (s, 1H), 6.54 (s, 1H),5.92-5.85 (m, 1H), 3.86-3.76 (m, 2H), 3.69 (s, 3H), 3.24-3.12 (m, 2H),2.30-2.20 (m, 1H), 2.03-1.94 (m, 1H), 1.65-1.56 (m, 2H), 1.42-1.18 (m,3H).

Example 954-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 1.24 g (purity 73%) of the racemate fromExample 94 gave 57.6 mg of the title compound Example 95 (enantiomer 1):Chiral HPLC: R_(t)=3.77 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50%carbon dioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

Example 964-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 1.24 g (purity 73%) of the racemate fromExample 94 gave 132 mg of the title compound Example 96 (enantiomer 2):Chiral HPLC: R_(t)=4.17 min; 98% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50%carbon dioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

Example 974-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoicacid (mixture of racemic diastereomers)

712 mg (purity 85%, 1.02 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 2. Yield: 209 mg (38% of theory)

LC/MS [Method 2]: R_(t)=2.81 min; MS (ESIpos): m/z=536 (M+H)⁺;R_(t)=2.88 min; MS (ESIpos): m/z=536 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.86/10.83 (2×s, 1H), 8.00 (d, 1H),7.92 (d, 2H), 7.81-7.70 (m, 4H), 7.53/7.50 (2×s, 1H), 6.56/6.55 (2×s,1H), 5.86/5.82 (2×dd, 1H), 3.87-3.74 (m, 1H), 3.75-3.66 (m, 1H), 3.70(s, 3H), 3.17-3.02 (m, 1H), 2.23-2.08 (m, 1H), 2.02-1.77 (m, 2H),1.64-1.49 (m, 1H), 1.48-1.30 (m, 2H), 1.30-1.13 (m, 1H).

Example 984-(2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoylamino)benzoic acid (enantiomer 1 of the first diastereomer)

Diastereomer and enantiomer separation of 205 mg of the mixture fromExample 97 gave 27 mg of the title compound Example 98 (enantiomer 1 ofthe first diastereomer): Chiral HPLC: R_(t)=9.48 min; >99% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250 mm×20 mm;mobile phase: 50% isohexane, 50% ethanol+0.2% TFA; temperature: 30° C.;flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; flow rate: 3ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.83 (s, 1H),8.00 (d, 1H), 7.92 (d, 2H), 7.81-7.70 (m, 4H), 7.53 (s, 1H), 6.56 (s,1H), 5.82 (dd, 1H), 3.87-3.78 (m, 1H), 3.76-3.66 (m, 1H), 3.70 (s, 3H),3.30-3.21 (m, 1H), 3.12 (dd, 1H), 2.18-2.07 (m, 1H), 2.02-1.91 (m, 1H),1.86-1.75 (m, 1H), 1.59-1.49 (m, 1H), 1.49-1.30 (m, 2H), 1.29-1.13 (m,1H).

Example 994-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoicacid (enantiomer 1 of the second diastereomer)

Diastereomer and enantiomer separation of 205 mg of the mixture fromExample 97 gave 27 mg (purity 88%) of the title compound Example 99(enantiomer 1 of the second diastereomer): Chiral HPLC: R_(t)=10.86min; >99% ee.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250 mm×20 mm;mobile phase: 50% isohexane, 50% ethanol+0.2% TFA; temperature: 30° C.;flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; flow rate: 3ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.86 (s, 1H),8.00 (d, 1H), 7.92 (d, 2H), 7.81-7.70 (m, 4H), 7.50 (s, 1H), 6.55 (s,1H), 5.86 (dd, 1H), 3.81-3.74 (m, 1H), 3.74-3.65 (m, 1H), 3.70 (s, 3H),3.33-3.22 (m, 1H), 3.07 (dd, 1H), 2.23-2.11 (m, 1H), 1.94-1.78 (m, 2H),1.64-1.54 (m, 1H), 1.44-1.20 (m, 3H).

Example 1004-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-3-yl)propanoyl}amino)benzoicacid (mixture of enantiomer 2 of the first diastereomer and enantiomer 2of the second diastereomer)

Diastereomer and enantiomer separation of 205 mg of the mixture fromExample 97 gave 74 mg (purity 95%) of the title compound Example 100(mixture of enantiomer 2 of the first diastereomer and enantiomer 2 ofthe second diastereomer): Chiral HPLC: R_(t)=14.38 min.

Separation method: column: Daicel Chiralpak AZ-H 5 μm 250 mm×20 mm;mobile phase: 50% isohexane, 50% ethanol+0.2% TFA; temperature: 30° C.;flow rate: 15 ml/min; UV detection: 220 nm.

Analysis: column: Daicel Chiralpak AZ-H 5 μm 250 mm×4.6 mm; mobilephase: 50% isohexane, 50% ethanol+0.2% TFA+1% water; flow rate: 3ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (br. s, 1H), 10.86/10.83 (2×s,1H), 8.00 (d, 1H), 7.92 (d, 2H), 7.81-7.70 (m, 4H), 7.53/7.50 (2×s, 1H),6.56/6.55 (2×s, 1H), 5.86/5.82 (2×dd, 1H), 3.87-3.74 (m, 1H), 3.74-3.65(m, 1H), 3.70 (s, 3H), 3.34-3.22 (m, 1H), 3.17-3.02 (m, 1H), 2.23-2.08(m, 1H), 2.02-1.77 (m, 2H), 1.64-1.49 (m, 1H), 1.48-1.30 (m, 2H),1.30-1.13 (m, 1H).

Example 101({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (mixture of racemic diastereomers)

1.24 g (2.25 mmol) of methyl({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate(mixture of racemic diastereomers) in 30 ml of methanol/water (4/1) werereacted with 1.47 g (4.51 mmol) of caesium carbonate according toGeneral Method 4. Yield: 1.17 g (85% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIneg): m/z=534 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8/10.7 (2×s, 1H),8.02-7.98 (m, 1H), 7.93-7.87 (m, 2H), 7.80-7.71 (m, 4H), 7.53/7.49 (2×s,1H), 6.52/6.51 (2×s, 1H), 5.85-5.71 (m, 1H), 3.90-3.78 (m, 1H),3.69-3.68 (2×s, 3H), 3.29-3.15 (m, 1H), 3.13-3.05 (m, 1H), 2.42-2.11 (m,2H), 1.78-1.70 (m, 1H), 1.67-1.56 (m, 1H), 1.47-1.35 (m, 3H), 1.30-1.19(m, 1H).

Example 102({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomer 1 of the first diastereomer)

Diastereomer and enantiomer separation of 1.17 g of the mixture fromExample 101 gave 231 mg of the title compound Example 102 (enantiomer 1of the first diastereomer): Chiral HPLC: R_(t)=9.96 min; 87% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (s, 1H), 10.7 (s, 1H), 8.00 (d,1H), 7.90 (d, 2H), 7.77-7.72 (m, 4H), 7.49 (s, 1H), 6.51 (s, 1H),5.78-5.71 (m, 1H), 3.84-3.79 (m, 1H), 3.69 (s, 3H), 3.23-3.15 (m, 1H),3.13-3.05 (m, 1H), 2.42-2.32 (m, 1H), 2.26-2.18 (m, 1H), 1.78-1.71 (m,1H), 1.62-1.56 (m, 1H), 1.46-1.37 (m, 3H), 1.30-1.20 (m, 1H).

Example 103({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomer 1 of the second diastereomer)

Diastereomer and enantiomer separation of 1.17 g of the mixture fromExample 101 gave 54 mg of the title compound Example 103 (enantiomer 1of the second diastereomer): Chiral HPLC: R_(t)=15.34 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.7 (s, 1H), 7.99 (d,1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.74-7.71 (m, 2H), 7.52 (s, 1H), 6.52(s, 1H), 5.82 (t, 1H), 3.90-3.84 (m, 1H), 3.68 (s, 3H), 3.28-3.22 (m,2H), 2.34-2.27 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.73 (m, 1H), 1.67-1.60(m, 1H), 1.47-1.36 (m, 3H), 1.33-1.23 (m, 1H).

Example 104({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomer 2 of the second diastereomer)

Diastereomer and enantiomer separation of 1.17 g of the mixture fromExample 101 gave 91 mg of the title compound Example 104 (enantiomer 2of the second diastereomer): Chiral HPLC: R_(t)=20.83 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.7 (s, 1H), 7.99 (d,1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.74-7.71 (m, 2H), 7.52 (s, 1H), 6.52(s, 1H), 5.82 (t, 1H), 3.90-3.84 (m, 1H), 3.68 (s, 3H), 3.28-3.22 (m,2H), 2.34-2.27 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.73 (m, 1H), 1.67-1.60(m, 1H), 1.47-1.36 (m, 3H), 1.33-1.23 (m, 1H).

Example 105({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomer 2 of the first diastereomer)

Diastereomer and enantiomer separation of 1.17 g of the mixture fromExample 101 gave 183 mg of the title compound Example 105 (enantiomer 2of the first diastereomer): Chiral HPLC: R_(t)=27.14 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 40° C.; flow rate: 3ml/min; UV detection: 210 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (s, 1H), 10.7 (s, 1H), 8.00 (d,1H), 7.90 (d, 2H), 7.77-7.72 (m, 4H), 7.49 (s, 1H), 6.51 (s, 1H),5.78-5.71 (m, 1H), 3.84-3.79 (m, 1H), 3.69 (s, 3H), 3.23-3.15 (m, 1H),3.13-3.05 (m, 1H), 2.42-2.32 (m, 1H), 2.26-2.18 (m, 1H), 1.78-1.71 (m,1H), 1.62-1.56 (m, 1H), 1.46-1.37 (m, 3H), 1.30-1.20 (m, 1H).

Example 1064-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoyl}amino)benzoicacid (mixture of racemic diastereomers)

103 mg (0.17 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,4-dioxan-2-yl)propanoyl}amino)benzoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 2. Yield: 60 mg (64% of theory)

LC/MS [Method 8]: R_(t)=1.12 min; MS (ESIneg): m/z=536 (M−H)⁻;R_(t)=1.13 min; MS (ESIneg): m/z=536 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.75/10.73 (2×s,1H), 8.03-7.97 (m, 1H), 7.94-7.86 (m, 2H), 7.80-7.70 (m, 4H), 7.53/7.48(2×s, 1H), 6.54/6.53 (2×s, 1H), 5.83-5.73 (m, 1H), 3.79-3.65 (m, 2H),3.70/3.68 (2×s, 3H), 3.65-3.56 (m, 1H), 3.55-3.39 (m, 2H), 3.30-3.20 (m,2H), 2.41-2.09 (m, 2H).

Example 1074-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoyl}amino)benzoicacid (racemate)

114 mg (211 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoyl}amino)benzoate(racemate) and 325 μl (4.22 mmol) of TFA were reacted according toGeneral Method 2. The crude product was purified by preparative HPLC[column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase:acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 45 mg (44%of theory)

LC/MS [Method 1]: R_(t)=0.91 min; MS (ESIneg): m/z=482 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.72 (m, 4H), 7.52 (s, 1H), 6.55 (s, 1H),5.85 (t, 1H), 4.67-4.49 (m, 1H), 4.48-4.29 (m, 1H), 3.69 (s, 3H),2.69-2.55 (m, 2H).

Example 1084-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoyl}amino)benzoicacid (racemate)

80 mg (151 μmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoyl}amino)benzoate(racemate) in 2 ml of methanol/water (4/1) were reacted with 326 mg (302μmol) of caesium carbonate according to General Method 4. The crudeproduct was purified by preparative HPLC [column: Chromatorex C18, 10μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 18 mg (23% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIneg): m/z=500 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.7 (s, 1H), 8.00(d, 1H), 7.91 (d, 2H), 7.76-7.70 (m, 4H), 7.56 (s, 1H), 6.55 (s, 1H),6.15 (tt, 1H), 5.91 (dd, 1H), 3.69 (s, 3H), 2.99-2.75 (m, 2H).

Example 1094-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoyl}amino)benzoicacid (racemate)

21 mg (38 μmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoyl}amino)benzoate(racemate) in 0.75 ml of methanol/water (4/1) were reacted with 25 mg(77 μmol) of caesium carbonate according to General Method 4. The crudeproduct was purified by preparative HPLC [column: Chromatorex C18, 10μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 9 mg (46% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIneg): m/z=518 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.92 (d, 2H), 7.75-7.72 (m, 4H), 7.63 (s, 1H), 6.56 (s, 1H),6.11-6.05 (m, 1H), 3.69 (s, 3H), 3.56-3.25 (m, 2H).

Example 1104-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoyl}amino)benzoicacid (mixture of racemic diastereomers)

170 mg (purity 91%, 0.29 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluoropentanoyl}amino)benzoate(mixture of racemic diastereomers) were hydrolysed with lithiumhydroxide according to General Method 3. Yield: 67 mg (45% of theory)

LC/MS [Method 8]: R_(t)=1.19 min; MS (ESIpos): m/z=498 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.83 (s, 1H), 8.00 (d, 1H),7.95-7.87 (m, 2H), 7.81-7.70 (m, 4H), 7.55/7.51 (2×s, 1H), 6.54 (s, 1H),5.94-5.83 (m, 1H), 4.84-4.45 (2×dm, 2H), 3.69 (s, 3H), 2.46-2.41 (m,1H), 1.39/1.33 (2×t, 3H).

Example 1114-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoyl}amino)benzoicacid (mixture of racemic diastereomers)

48 mg (0.08 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoyl}amino)benzoate(mixture of racemic diastereomers) were hydrolysed with TFA according toGeneral Method 2. Yield: 24 mg (56% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=548 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.89/10.78 (2×s, 1H), 8.00 (d, 1H),7.96-7.88 (m, 2H), 7.81-7.70 (m, 4H), 7.53 (s, 1H), 6.59/6.58 (2×s, 1H),5.91/5.78 (2×dd, 1H), 3.69/3.67 (2×s, 3H), 2.72-2.62 (m, 1H), 2.44-2.31(m, 1H), 2.22-1.98 (m, 1H), 1.19/1.14 (2×d, 3H).

Example 1124-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoyl}amino)benzoicacid (racemate)

99 mg (176 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoyl}amino)benzoate(racemate) and 270 μl (3.51 μmol) of TFA were reacted according toGeneral Method 2. The crude product was purified by preparative HPLC[column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase:acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 57 mg (64%of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIneg): m/z=506 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.9 (s, 1H), 7.99 (d,1H), 7.91 (d, 2H), 7.77 (d, 2H), 7.74-7.71 (m, 2H), 7.60 (s, 1H), 6.54(s, 1H), 5.99 (dd, 1H), 3.70 (s, 3H), 2.12 (dd, 1H), 2.03 (dd, 1H), 0.92(s, 9H).

Example 1134-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoicacid (mixture of racemic diastereomers)

74.0 mg (127 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoate(mixture of racemic diastereomers) and 195 μl (2.53 mmol) of TFA werereacted according to General Method 2. The crude product was purified bypreparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobilephase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 45mg (52% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIneg): m/z=526 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8/10.7 (2×s, 1H),8.00 (d, 1H), 7.93-7.90 (m, 2H), 7.77-7.71 (m, 4H), 7.53 (s, 1H), 6.56(s, 1H), 5.80-5.70 (m, 1H), 3.70/3.69 (2×s, 3H), 2.60-2.37 (m, 1H),2.30-2.09 (2×m, 1H), 1.70-1.49 (m, 2H), 1.32-1.05 (2×m, 1H).

Example 1144-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoicacid (enantiomer 1 of the first diastereomer and enantiomer 1 of thesecond diastereomer)

Enantiomer separation of 44 mg of the mixture of racemic diastereomersfrom Example 113 gave 15 mg of the title compound Example 114: ChiralHPLC: R_(t)=5.42/5.81 min; 99% ee, diastereomer ratio 1:1.

Separation method: column: AZ-H 5 μm 250 mm×20 mm; mobile phase: 50%isohexane, 50% 2-propanol+0.2% TFA+1% water; temperature: 30° C.; flowrate: 20 ml/min; UV detection: 220 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 30° C.; flow rate: 1ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8/10.7 (2×s, 1H),8.00 (d, 1H), 7.93-7.90 (m, 2H), 7.77-7.71 (m, 4H), 7.53 (s, 1H), 6.56(s, 1H), 5.80-5.70 (m, 1H), 3.70/3.69 (2×s, 3H), 2.60-2.37 (m, 1H),2.30-2.09 (2×m, 1H), 1.70-1.49 (m, 2H), 1.32-1.05 (2×m, 1H).

Example 1154-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoyl}amino)benzoicacid (enantiomer 2 of the first diastereomer and enantiomer 2 of thesecond diastereomer)

Enantiomer separation of 44 mg of the mixture of racemic diastereomersfrom Example 113 gave 15 mg of the title compound Example 115: ChiralHPLC: R_(t)=8.75/9.79 min; 99% ee, diastereomer ratio 1:1.

Separation method: column: AZ-H 5 μm 250 mm×20 mm; mobile phase: 50%isohexane, 50% 2-propanol+0.2% TFA+1% water; temperature: 30° C.; flowrate: 20 ml/min; UV detection: 220 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% 2-propanol+0.2% TFA+1% water; temperature: 30° C.; flow rate: 1ml/min; UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8/10.7 (2×s, 1H),8.00 (d, 1H), 7.93-7.90 (m, 2H), 7.77-7.71 (m, 4H), 7.53 (s, 1H), 6.56(s, 1H), 5.80-5.70 (m, 1H), 3.70/3.69 (2×s, 3H), 2.60-2.37 (m, 1H),2.30-2.09 (2×m, 1H), 1.70-1.49 (m, 2H), 1.32-1.05 (2×m, 1H).

Example 1164-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoyl}amino)benzoicacid (racemate)

100 mg (178 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1-methylcyclopropyl)propanoyl}amino)benzoate(racemate) and 274 μl (3.56 mmol) of TFA were reacted according toGeneral Method 2. The reaction mixture was purified by preparative HPLC[column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase:acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 107 mg (27%of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIneg): m/z=504 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.91 (d, 2H), 7.79-7.72 (m, 4H), 7.55 (s, 1H), 6.53 (s, 1H), 5.97(dd, 1H), 3.68 (s, 3H), 2.20 (dd, 1H), 2.04 (dd, 1H), 1.08 (s, 3H),0.35-0.25 (m, 2H), 0.21-0.12 (m, 2H).

Example 1174-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)benzoicacid (racemate)

64 mg (purity 86%, 0.10 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 33 mg (67% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=506 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.80 (s, 1H), 8.00(s, 1H), 7.91 (d, 2H), 7.80-7.70 (m, 4H), 7.51 (s, 1H), 6.51 (s, 1H),5.75-5.65 (m, 1H), 3.69 (s, 3H), 2.35-2.16 (m, 3H), 2.01-1.88 (m, 2H),1.85-1.60 (m, 4H).

Example 1184-({[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetyl}amino)benzoicacid (racemate)

260 mg (0.48 mmol) of tert-butyl4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 184 mg (79% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=482 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.81 (br. s, 1H), 10.72 (s, 1H),8.01 (d, 1H), 7.94 (d, 2H), 7.84-7.71 (m, 4H), 7.35 (s, 1H), 6.57 (s,1H), 6.41 (s, 1H), 3.82-3.73 (m, 1H), 3.73-3.62 (m, 1H), 3.67 (s, 3H),1.27 (t, 3H).

Example 1194-({[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)benzoicacid

49.0 mg (99.0 μmol) of tert-butyl4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetyl}amino)benzoateand 153 μl (1.98 mmol) of TFA were reacted according to General Method2. Yield: 20 mg (44% of theory)

LC/MS [Method 1]: R_(t)=0.81 min; MS (ESIneg): m/z=436 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (s, 1H), 10.7 (s, 1H), 8.01 (d,1H), 7.92 (d, 2H), 7.75-7.71 (m, 4H), 7.60 (s, 1H), 6.52 (s, 1H), 4.82(s, 2H), 3.64 (s, 3H).

Example 1204-[(2-{4-[5-Chloro-2-(trifluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

155 mg (0.23 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoatewere hydrolysed with TFA according to General Method 2. Yield: 67 mg(purity 94%, 54% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=511 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (br. s, 1H), 10.68 (s, 1H),7.91 (d, 2H), 7.73 (d, 2H), 7.65 (dd, 1H), 7.59 (d, 1H), 7.51 (dd, 1H),7.40 (s, 1H), 6.41 (s, 1H), 5.59 (q, 1H), 3.65 (s, 3H), 1.72 (d, 3H).

Example 1214-({2-[4-(2-Bromo-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

72 mg (purity 73%, 0.09 mmol) of tert-butyl4-({2-[4-(2-bromo-5-chlorophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 20 mg (42% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=505 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.70 (s, 1H), 7.91(d, 2H), 7.78-7.69 (m, 3H), 7.51-7.41 (m, 2H), 7.40 (s, 1H), 6.32 (s,1H), 5.61 (q, 1H), 3.66 (s, 3H), 1.72 (d, 3H).

Example 1224-({2-[4-(5-Chloro-2-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

105 mg (purity 91%, 0.19 mmol) of tert-butyl4-({2-[4-(5-chloro-2-methylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 47 mg (60% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=441 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.67 (s, 1H), 7.91(d, 2H), 7.74 (d, 2H), 7.42-7.34 (m, 2H), 7.31 (d, 1H), 7.22 (d, 1H),6.26 (s, 1H), 5.60 (q, 1H), 3.63 (s, 3H), 2.11 (s, 3H), 1.72 (d, 3H).

Example 1234-[(2-{4-[5-Chloro-2-(trifluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

145 mg (purity 84%, 0.22 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 41 mg (37% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=495 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.70/10.68 (2×s, 1H),7.91 (d, 2H), 7.87 (d, 1H), 7.79-7.69 (m, 3H), 7.58/7.54 (2×s, 1H), 7.37(s, 1H), 6.36/6.34 (2×s, 1H), 5.61 (q, 1H), 3.63 (s, 3H), 1.72 (2×d,3H).

Example 1244-({2-[4-(5-Chloro-2-cyclopropylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

114 mg (0.22 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 73 mg (78% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=467 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.68 (s, 1H), 7.91(d, 2H), 7.74 (d, 2H), 7.38 (s, 1H), 7.35 (dd, 1H), 7.19 (d, 1H), 6.95(d, 1H), 6.31 (s, 1H), 5.61 (q, 1H), 3.65 (s, 3H), 1.72 (d, 3H),1.70-1.59 (m, 1H), 0.85 (d, 2H), 0.65 (br. s, 2H).

Example 1254-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoicacid (mixture of racemic diastereomers)

631 mg (1.14 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoate(mixture of racemic diastereomers) in 22.5 ml of methanol/water (4/1)were reacted with 745 mg (2.29 mmol) of caesium carbonate according toGeneral Method 4. Yield: 580 mg (purity 87%, 84% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=524 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (br. s, 1H), 10.8 (2×s, 1H),8.01-7.89 (m, 1H), 7.93-7.88 (m, 2H), 7.80-7.72 (m, 4H), 7.59/7.52 (2×s,1H), 6.54 (s, 1 h), 5.88-5.81 (m, 1H), 3.69 (s, 3H), 3.19/3.13 (2×s,3H), 3.08-3.02/2.95-2.89 (2×m, 1H), 2.44-2.31 (m, 1H) 2.27-2.16 (m, 1H),1.62-1.45 (m, 2H), 0.86/0.85 (2×t, 3H).

Example 1264-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-hydroxybutanoyl}amino)benzoicacid (racemate)

266 mg (355 μmol) of ethyl4-[(4-{[tert-butyl(diphenyl)silyl]oxy}-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl)amino]benzoate(racemate) in 7 ml of methanol/water (4/1) were reacted with 232 mg (711μmol) of caesium carbonate according to General Method 4. The crudeproduct was purified by preparative HPLC [column: Chromatorex C18, 10μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 16.5 mg (9% of theory)

LC/MS [Method 1]: R_(t)=0.80 min; MS (ESIpos): m/z=482 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.7 (s, 1H), 8.00(d, 1H), 7.90 (d, 2H), 7.78-7.71 (m, 4H), 7.49 (s, 1H), 6.53 (s, 1H),5.76 (dd, 1H), 4.76 (t, 1H), 3.69 (s, 3H), 3.51-3.38 (m, 2H), 2.38-2.26(m, 2H).

Example 1274-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoicacid (racemate)

47 mg (0.09 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 33 mg (78% of theory)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=493 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (br. s, 1H), 10.68 (s, 1H),7.91 (d, 2H), 7.73 (d, 2H), 7.58 (dd, 1H), 7.47 (d, 1H), 7.36 (s, 1H),7.30 (d, 1H), 7.16 (t, 1H), 6.38 (s, 1H), 5.59 (q, 1H), 3.65 (s, 3H),1.72 (d, 3H).

Example 1284-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]benzoicacid (racemate)

127 mg (0.23 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl)amino]benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 72 mg (63% of theory)

LC/MS [Method 1]: R_(t)=0.99 min; MS (ESIpos): m/z=507 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.75 (br. s, 1H), 10.78 (s, 1H),7.91 (d, 2H), 7.75 (d, 2H), 7.58 (dd, 1H), 7.49 (dd, 1H), 7.39 (s, 1H),7.30 (d, 1H), 7.13 (t, 1H), 6.40 (s, 1H), 5.63 (dd, 1H), 3.64 (s, 3H),2.24-2.06 (m, 2H), 0.90 (t, 3H).

Example 1294-({2-[4-(5-Chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

32 mg (purity 89%, 0.06 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-ethoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 11 mg (44% of theory)

LC/MS [Method 3]: R_(t)=2.25 min; MS (ESIpos): m/z=466 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.70 (s, 1H), 8.01(d, 1H), 7.91 (d, 2H), 7.78-7.68 (m, 4H), 7.49 (s, 1H), 6.53 (s, 1H),5.60 (q, 1H), 3.92 (q, 2H), 1.72 (d, 3H), 1.18 (t, 3H).

Example 1304-({2-[4-(5-Chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

99 mg (0.18 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 75 mg (84% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=488 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.78 (s, 1H), 8.05(d, 1H), 7.99 (s, 1H), 7.91 (d, 2H), 7.82-7.68 (m, 4H), 6.89 (t, 1H),6.65 (s, 1H), 5.57 (q, 1H), 1.72 (d, 3H).

Example 1314-({2-[4-(5-Chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoyl}amino)benzoicacid (racemate)

113 mg (0.14 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 39 mg (purity 90%, 49% of theory)

LC/MS [Method 1]: R_(t)=0.98 min; MS (ESIpos): m/z=520 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.73 (s, 1H),8.03 (d, 1H), 7.92 (d, 2H), 7.82-7.70 (m, 5H), 6.59 (s, 1H), 5.58 (q,1H), 4.66 (dq, 2H), 1.74 (d, 3H).

Example 1324-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-hydroxycyclohexyl)propanoylamino)benzoic acid (mixture of racemic diastereomers)

341 mg (473 μmol) of tert-butyl4-({3-(4-[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate(mixture of racemic diastereomers) were reacted with 912 μl (11.8 mmol)of TFA according to General Method 2. The crude product was purified bypreparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobilephase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 107mg (27% of theory)

LC/MS [Method 1]: R_(t)=0.87-0.89 min; MS (ESIneg): m/z=548 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (2×s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.71 (m, 4H), 7.50/7.49 (2×s, 1H), 6.54/6.53(2×s, 1H), 5.88-5.81 (m, 1H), 4.45/4.28 (2×d, 1H), 3.69 (s, 3H),2.23-2.13 (m, 1H), 2.04-1.84 (m, 1H), 1.82-1.69 (m, 2H), 1.63-1.28 (m,4H), 1.24-1.13 (m, 1H), 1.10-0.95 (m, 2H).

Example 1334-(2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-hydroxycyclohexyl)propanoylamino)benzoic acid (enantiomer 1 of the first diastereomer andenantiomer 1 of the second diastereomer)

Enantiomer separation of 107 mg of the mixture of racemic diastereomersfrom Example 132 gave 23 mg of the title compound Example 133: ChiralHPLC: R_(t)=5.77/5.84 min; 99% ee, diastereomer ratio: 1:1.

Separation method: column: AZ-H 5 μm 250 mm×20 mm; mobile phase: 50%isohexane, 50% ethanol+0.2% acetic acid; temperature: 30° C.; flow rate:15 ml/min; UV detection: 230 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% ethanol+0.2% TFA+1% water; temperature: 30° C.; flow rate: 1 ml/min;UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (2×s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.71 (m, 4H), 7.50/7.49 (2×s, 1H), 6.54/6.53(2×s, 1H), 5.88-5.81 (m, 1H), 4.45/4.28 (2×d, 1H), 3.69 (s, 3H),2.23-2.13 (m, 1H), 2.04-1.84 (m, 1H), 1.82-1.69 (m, 2H), 1.63-1.28 (m,4H), 1.24-1.13 (m, 1H), 1.10-0.95 (m, 2H).

Example 1344-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-hydroxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 2 of the first diastereomer)

Enantiomer separation of 107 mg of the mixture of racemic diastereomersfrom Example 132 gave 11 mg of the title compound Example 134: ChiralHPLC: R_(t)=9.44 min; 99% ee.

Separation method: column: AZ-H 5 μm 250 mm×20 mm; mobile phase: 50%isohexane, 50% ethanol+0.2% acetic acid; temperature: 30° C.; flow rate:15 ml/min; UV detection: 230 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% ethanol+0.2% TFA+1% water; temperature: 30° C.; flow rate: 1 ml/min;UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.91 (d, 2H), 7.78-7.71 (m, 4H), 7.49 (s, 1H), 6.54 (s, 1H),5.87-5.80 (m, 1H), 4.45 (d, 1H), 3.69 (s, 3H), 2.23-2.13 (m, 1H),1.95-1.85 (m, 1H), 1.84-1.69 (m, 4H), 1.10-0.93 (m, 5H).

Example 1354-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-hydroxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 2 of the second diastereomer)

Enantiomer separation of 107 mg of the mixture of racemic diastereomersfrom Example 132 gave 14 mg of the title compound Example 135: ChiralHPLC: R_(t)=11.77 min; 89% ee.

Separation method: column: AZ-H 5 μm 250 mm×20 mm; mobile phase: 50%isohexane, 50% ethanol+0.2% acetic acid; temperature: 30° C.; flow rate:15 ml/min; UV detection: 230 nm.

Analysis: column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 50% isohexane,50% ethanol+0.2% TFA+1% water; temperature: 30° C.; flow rate: 1 ml/min;UV detection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.91 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.53 (s, 1H),5.89-5.81 (m, 1H), 4.29 (d, 1H), 3.69 (s, 3H), 2.22-2.12 (m, 1H),2.05-1.95 (m, 1H), 1.64-1.14 (m, 9H).

Example 1364-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (racemate)

151 mg (248 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoate(racemate) and 574 μl (7.45 mmol) of TFA were reacted according toGeneral Method 2. The crude product was purified by preparative HPLC[column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase:acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 65 mg (47%of theory)

LC/MS [Method 1]: R_(t)=1.02 min; MS (ESIneg): m/z=548 (M−H)⁻

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 8.00 (d,1H), 7.91 (d, 2H), 7.76-7.70 (m, 4H), 7.51 (s, 1H), 6.56 (s, 1H), 5.81(t, 1H), 4.20-4.15 (m, 1H), 4.03-3.99 (m, 1H), 3.69 (s, 3H), 2.66-2.60(m, 2H).

Example 1374-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 165 mg of the mixture of racemic diastereomersfrom Example 136 gave 65 mg of the title compound Example 137: ChiralHPLC: R_(t)=1.00 min; 99% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×30 mm; mobile phase:70% carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 100ml/min; UV detection: 210 nm.

Analysis (SFC): column: AZ-3 5 μm 250 mm×4.6 mm; mobile phase: 85%carbon dioxide, 15% ethanol; temperature: 30° C.; flow rate: 3 ml/min;UV detection: 220 nm.

Example 1384-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 165 mg of the mixture of racemic diastereomersfrom Example 136 gave 69 mg of the title compound Example 138: ChiralHPLC: R_(t)=2.01 min; 94% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×30 mm; mobile phase:70% carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 100ml/min; UV detection: 210 nm.

Analysis (SFC): column: AZ-3 5 μm 250 mm×4.6 mm; mobile phase: 85%carbon dioxide, 15% ethanol; temperature: 30° C.; flow rate: 3 ml/min;UV detection: 220 nm.

Example 1392-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)-N-[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]propanamide(racemate)

37.4 mg (89.6 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoicacid (racemate), 15.9 mg (89.6 μmol) of3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one, 12.7 mg (89.6 μmol) ofOxima and 14.0 μl (89.6 μmol) of DIC in 950 μl of dimethylformamide werereacted according to General Method 5. The crude product was purified bypreparative HPLC [column: Chromatorex C18, 10 nm, 125 mm×30 mm, mobilephase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10%acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90%acetonitrile)] and then using Method 10. Yield: 2 mg (4% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=576 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.9 (br. s, 1H), 10.9 (s, 1H), 7.99(d, 1H), 7.83 (d, 2H), 7.79 (m, 2H), 7.74-7.70 (m, 3H), 6.54 (s, 1H),5.82-5.76 (m, 1H), 4.40 (d, 1H), 4.26 (d, 1H), 4.15 (d, 1H), 4.05 (d,1H), 3.72 (s, 3H), 2.56-2.44 (m, 2H), 1.83-1.75 (m, 2H), 0.90 (t, 3H).

Example 1404-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoyl}amino)benzoicacid (racemate)

79 mg (purity 91%, 0.14 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](3,3,4,4,4-pentadeutero)butanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 30 mg (46% of theory)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=471 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.74 (br. s, 1H), 10.78 (s, 1H),8.00 (d, 1H), 7.91 (d, 2H), 7.79-7.70 (m, 4H), 7.49 (s, 1H), 6.54 (s,1H), 5.63 (s, 1H), 3.69 (s, 3H).

Example 1414-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoicacid (enantiomer 1 of the first diastereomer)

Diastereomer and enantiomer separation of 528 mg of the mixture fromExample 125 gave, after further preparative HPLC, 32.5 mg of the titlecompound Example 141 (enantiomer 1 of the first diastereomer): ChiralHPLC: R_(t)=3.44 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:85% carbon dioxide, 15% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50% carbondioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.90 (d, 2H), 7.79-7.71 (m, 4H), 7.52 (s, 1H), 6.54 (s, 1H),5.87-5.81 (m, 1H), 3.68 (s, 3H), 3.13 (s, 3H), 2.96-2.89 (m, 1H),2.43-2.31 (m, 1H), 2.26-2.17 (m, 1H), 1.58-1.46 (m, 2H), 0.85 (t, 3H).

Example 1424-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoicacid (enantiomer 2 of the first diastereomer)

Diastereomer and enantiomer separation of 528 mg of the mixture fromExample 125 gave, after further preparative HPLC, 32.4 mg of the titlecompound Example 142 (enantiomer 2 of the first diastereomer): ChiralHPLC: R_(t)=3.53 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:85% carbon dioxide, 15% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50% carbondioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.90 (d, 2H), 7.79-7.71 (m, 4H), 7.52 (s, 1H), 6.54 (s, 1H),5.87-5.81 (m, 1H), 3.68 (s, 3H), 3.13 (s, 3H), 2.96-2.89 (m, 1H),2.43-2.31 (m, 1H), 2.26-2.17 (m, 1H), 1.58-1.46 (m, 2H), 0.85 (t, 3H).

Example 1434-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoicacid (enantiomer 1 of the second diastereomer)

Diastereomer and enantiomer separation of 528 mg of the mixture fromExample 125 gave, after further preparative HPLC, 25.9 mg of the titlecompound Example 143 (enantiomer 1 of the second diastereomer): ChiralHPLC: R_(t)=3.71 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:85% carbon dioxide, 15% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50% carbondioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.91 (d, 2H), 7.77 (d, 2H), 7.75-7.71 (m, 2H), 7.59 (s, 1H),6.54 (s, 1H), 5.86-5.81 (m, 1H), 3.68 (s, 3H), 3.19 (s, 3H), 3.09-3.02(m, 1H), 2.28-2.21 (m, 2H), 1.63-1.45 (m, 2H), 0.86 (t, 3H).

Example 1444-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoyl}amino)benzoicacid (enantiomer 2 of the second diastereomer)

Diastereomer and enantiomer separation of 528 mg of the mixture fromExample 125 gave, after further preparative HPLC, 21.9 mg of the titlecompound Example 144 (enantiomer 2 of the second diastereomer): ChiralHPLC: R_(t)=4.27 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:85% carbon dioxide, 15% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50% carbondioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3 ml/min; UVdetection: 220 nm.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.91 (d, 2H), 7.77 (d, 2H), 7.75-7.71 (m, 2H), 7.59 (s, 1H),6.54 (s, 1H), 5.86-5.81 (m, 1H), 3.68 (s, 3H), 3.19 (s, 3H), 3.09-3.02(m, 1H), 2.28-2.21 (m, 2H), 1.63-1.45 (m, 2H), 0.86 (t, 3H).

Example 1454-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoicacid (racemate)

157 mg (255 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoate(racemate) were hydrolysed with 393 μl (5.10 mmol) of trifluoroaceticacid according to General Method 2, and after preparative HPLC [column:Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1%formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)], the title compoundwas obtained. Yield: 94 mg (65% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIneg): m/z=558 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.92 (d, 2H), 7.78-7.71 (m, 4H), 7.52 (s, 1H), 6.55 (s, 1H),5.86-5.79 (m, 1H), 3.67 (s, 3H), 2.60-2.44 (m, 2H), 0.97-0.79 (m, 4H).

Example 1464-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 94 mg of the racemate from Example 145 gave29.9 mg of the title compound Example 146 (enantiomer 1): Chiral HPLC:R_(t)=3.71 min; 99% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×30 mm; mobile phase:75% carbon dioxide, 25% ethanol; temperature: 40° C.; flow rate: 100ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 80%carbon dioxide, 20% ethanol; temperature: 40° C.; flow rate: 3 ml/min;UV detection: 210 nm.

Example 1474-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 94 mg of the racemate from Example 145 gave27.8 mg of the title compound Example 147 (enantiomer 2): Chiral HPLC:R_(t)=5.32 min; 99% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×30 mm; mobile phase:75% carbon dioxide, 25% ethanol; temperature: 40° C.; flow rate: 100ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 80%carbon dioxide, 20% ethanol; temperature: 40° C.; flow rate: 3 ml/min;UV detection: 210 nm.

Example 1484-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoyl}amino)benzoicacid (racemate)

58 mg (0.09 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclobutyl]propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 35 mg (65% of theory)

LC/MS [Method 1]: R_(t)=1.09 min; MS (ESIpos): m/z=574 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.88 (s, 1H), 7.99 (d, 1H), 7.92 (d,2H), 7.81-7.70 (m, 4H), 7.58 (s, 1H), 6.58 (s, 1H), 5.95 (t, 1H), 3.68(s, 3H), 2.61 (dd, 1H), 2.48 (dd, 1H), 2.21 (t, 2H), 2.18-2.12 (m, 1H),2.12-2.02 (m, 1H), 1.99-1.83 (m, 2H).

Example 1494-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoyl}amino)benzoicacid (racemate)

175 mg (0.29 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3,3-difluorocyclobutyl)propanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 122 mg (77% of theory)

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=542 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (s, 1H), 10.79 (s, 1H), 8.00(d, 1H), 7.92 (d, 2H), 7.79-7.69 (m, 4H), 7.53 (s, 1H), 6.54 (s, 1H),5.73 (dd, 1H), 3.70 (s, 3H), 2.68-2.50 (m, 2H), 2.50-2.39 (m, 2H),2.39-2.21 (m, 2H), 2.08-1.95 (m, 1H).

Example 1504-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoyl}amino)benzoicacid (racemate)

25 mg (44 μmol) of allyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-methyloxetan-3-yl)propanoyl}amino)benzoate(racemate) and 48.2 μl (445 μmol) of N-methylaniline were initiallycharged in 1 ml of tetrahydrofuran, and the resulting solution wasdegassed. 5 mg (4 μmol) of tetrakis(triphenylphosphine)palladium(0) werethen added, and the mixture was stirred at room temperature for another30 min. The reaction solution was purified directly by preparative HPLC(neutral) and the title compound was obtained after final preparativethin-layer chromatography (ethyl acetate/cyclohexane=1:1). Yield: 10.1mg (purity 92%, 42% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=522 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 7.99(d, 1H), 7.92 (d, 2H), 7.77-7.71 (m, 4H), 7.66 (s, 1H), 6.52 (s, 1H),5.87 (dd, 1H), 4.46 (d, 1H), 4.29 (d, 1H), 4.11 (d, 1H), 3.95 (d, 1H),3.72 (s, 3H), 2.68 (dd, 1H), 2.37 (dd, 1H), 1.38 (s, 3H).

Example 1514-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoicacid (racemate)

69.0 mg (119 μmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(4-methyltetrahydro-2H-pyran-4-yl)propanoyl}amino)benzoate(racemate) in 4.3 ml of ethanol/water (3/1) were reacted with 198 mg(609 μmol) of caesium carbonate according to General Method 4, givingthe title compound after preparative HPLC [column: Chromatorex C18, 10μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient(0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 38 mg (57% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=550 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.9 (s, 1H), 7.98(d, 1H), 7.92 (d, 2H), 7.77 (d, 2H), 7.74-7.71 (m, 2H), 7.66 (s, 1H),6.52 (s, 1H), 6.05 (dd, 1H), 3.71 (s, 3H), 3.65-3.40 (m, 4H), 2.29 (dd,1H), 2.04 (dd, 1H), 1.57-1.49 (m, 1H), 1.41-1.25 (m, 2H), 1.16-1.09 (m,1H), 1.03 (s, 3H).

Example 1524-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (racemate)

2.10 g (3.55 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoate(racemate) in 129 ml of ethanol/water (2.6/1) were reacted with 5.89 g(18.1 mmol) of caesium carbonate according to General Method 4. Aftercomplete conversion, the pH was adjusted to 5-6 with hydrochloric acid(1N) and the mixture was stirred for another 30 min. The precipitate wasfiltered off with suction, washed with a little water and dried underhigh vacuum and it corresponded to the title compound. Yield: 1.24 g(60% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=564 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 7.99 (d,1H), 7.92 (d, 2H), 7.79-7.71 (m, 4H), 7.50 (s, 1H), 6.53 (s, 1H),5.88-5.82 (m, 1H), 3.69 (s, 3H), 3.19 (s, 3H), 2.23-2.13 (m, 1H),2.02-1.92 (m, 1H), 1.82-1.70 (m, 2H), 1.52-1.42 (m, 2H), 1.40-1.16 (m,5H).

Example 1534-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 1.24 g of the racemate from Example 152 gave562 mg of the title compound Example 153 (enantiomer 1): Chiral HPLC:R_(t)=3.18 min; 99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50%carbon dioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3ml/min; UV detection: 220 nm.

Example 1544-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 1.24 g of the racemate from Example 152 gave566 mg of the title compound Example 154 (enantiomer 2): Chiral HPLC:R_(t)=3.82 min; 98% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:80% carbon dioxide, 20% 2-propanol; temperature: 40° C.; flow rate: 80ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AD-3 5 μm 250 mm×4.6 mm; mobile phase: 95-50%carbon dioxide, 5-50% 2-propanol; temperature: 40° C.; flow rate: 3ml/min; UV detection: 220 nm.

Example 1554-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (racemate)

1.10 g (1.86 mmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoate(racemate) in 67 ml of ethanol/water (2.6/1) were reacted with 3.09 g(9.48 mmol) of caesium carbonate according to General Method 4. Aftercomplete conversion, the pH was adjusted to 5-6 with hydrochloric acid(1N) and the mixture was stirred for another 30 min. The precipitate wasfiltered off with suction, washed with a little water and dried underhigh vacuum. Yield: 690 mg (purity 89%, 59% of theory)

100 mg of the crude product was purified by preparative HPLC [column:Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1%formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90%acetonitrile and a further 3 min 90% acetonitrile)], giving the titlecompound. Yield: 30 mg (3% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=564 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (s, 1H), 10.8 (s, 1H), 7.99 (d,1H), 7.91 (d, 2H), 7.77-7.71 (m, 4H), 7.49 (s, 1H), 6.54 (s, 1H),5.87-5.81 (m, 1H), 3.69 (s, 3H), 3.20 (s, 3H), 3.07-2.99 (m, 1H),2.24-2.15 (m, 1H), 2.00-1.88 (m, 3H), 1.85-1.73 (m, 2H), 1.15-0.88 (m,5H).

Example 1564-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of 586 mg of the racemate from Example 155 gave,after further preparative HPLC, 145 mg of the title compound Example 156(enantiomer 1): Chiral HPLC: R_(t)=5.62 min; 99% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×20 mm; mobile phase:75% carbon dioxide, 25% ethanol; temperature: 40° C.; flow rate: 100ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 3 ml/min;UV detection: 220 nm.

Example 1574-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(trans-4-methoxycyclohexyl)propanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of 586 mg of the racemate from Example 155 gave,after further preparative HPLC, 110 mg of the title compound Example 157(enantiomer 2): Chiral HPLC: R_(t)=8.17 min; 99% ee.

Separation method (SFC): column: AZ-H 5 μm 250 mm×20 mm; mobile phase:75% carbon dioxide, 25% ethanol; temperature: 40° C.; flow rate: 100ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis (SFC): column: AZ-H 5 μm 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; temperature: 40° C.; flow rate: 3 ml/min;UV detection: 220 nm.

Example 1582-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutyl-N-[4-(2-oxo-2,3-dihydro-1,3-oxazol-5-yl)phenyl]propanamide(racemate)

103 mg (purity 94%, 0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoicacid (racemate) and 55 mg (0.28 mmol, 1.1 eq.) of5-(4-aminophenyl)-1,3-oxazol-2(3H)-one were reacted according to GeneralMethod 1. The crude product was purified by preparative HPLC (ReprosilC18, water/acetonitrile gradient). Yield: 36 mg (27% of theory)

LC/MS [Method 8]: R_(t)=1.30 min; MS (ESIneg): m/z=543 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.78 (s, 1H), 10.59 (s, 1H), 8.00(d, 1H), 7.76-7.70 (m, 2H), 7.68 (d, 2H), 7.52 (s, 1H), 7.46 (d, 2H),7.40 (s, 1H), 6.51 (s, 1H), 5.68 (t, 1H), 3.69 (s, 3H), 2.30-2.17 (m,3H), 2.01-1.88 (m, 2H), 1.84-1.61 (m, 4H).

Example 1592-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutyl-N-(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)propanamide(racemate)

101 mg (0.16 mmol) of tert-butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 52 mg (62% of theory)

LC/MS [Method 1]: R_(t)=0.95 min; MS (ESIpos): m/z=532 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.73 (s, 1H), 10.21 (s, 1H), 8.00(d, 1H), 7.80-7.70 (m, 3H), 7.57 (d, 1H), 7.53 (s, 1H), 7.18 (dd, 1H),6.52 (s, 1H), 5.70 (t, 1H), 3.70 (s, 3H), 2.30-2.17 (m, 3H), 2.01-1.88(m, 2H), 1.84-1.61 (m, 4H).

Example 1604-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)benzoicacid (racemate)

95 mg (177 μmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (column: Chromatorex 125mm×30 mm, 10 μm, mobile phase: 0.1% aqueous ammonium formate solutionand acetonitrile, gradient 30% acetonitrile to 70% acetonitrile). Yield:28 mg (33% of theory)

LC/MS [Method 1]: R_(t)=1.00 min; MS (ESIpos): m/z=480 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.0 (s, 1H), 8.00 (d, 1H), 7.89 (d,2H), 7.78-7.71 (m, 4H), 7.65 (s, 1H), 6.56 (s, 1H), 5.52 (d, 1H), 3.69(s, 3H), 1.08 (d, 3H), 0.82 (d, 3H).

Example 1614-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-2-methylbenzoicacid (racemate)

105 mg (207 μmol) of methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-2-methylbenzoate(racemate) were dissolved in 4.0 ml of methanol. 0.83 ml of a 1N sodiumhydroxide solution was added and the mixture was heated to reflux for 1h. The reaction mixture was then concentrated under reduced pressure andthe residue was taken up in water and acidified with 1N aqueoushydrochloric acid. The mixture was extracted with ethyl acetate, theorganic phase was dried over sodium sulphate and the solvent was removedunder reduced pressure. The residue was purified by preparative HPLC(column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase: 0.1% aqueousammonium formate solution and acetonitrile, gradient 30% acetonitrile to70% acetonitrile). The isolated product was finally triturated withwater and filtered off with suction. Yield: 15 mg (15% of theory)

LC/MS [Method 1]: R_(t)=1.03 min; MS (ESIpos): m/z=494 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.6 (br. s, 1H), 10.9 (s, 1H), 8.00(d, 1H), 7.84 (d, 1H), 7.76-7.71 (m, 2H), 7.64-7.60 (m, 2H), 7.57 (dd,1H), 6.55 (s, 1H), 5.51 (d, 1H), 3.69 (s, 3H), 2.51 (s, 3H), 1.08 (d,3H), 0.82 (d, 3H).

Example 1626-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-1H-benzimidazole-2-carboxylicacid (racemate)

130 mg (237 μmol) of ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoyl}amino)-1H-benzimidazole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 3. Yield: 56 mg (44% of theory)

LC/MS [Method 1]: R_(t)=0.83 min; MS (ESIpos): m/z=520 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.9 (s, 1H), 8.20 (s, 1H), 8.14 (s,1H), 8.00 (d, 1H), 7.76 (d, 1H), 7.75-7.72 (m, 1H), 7.68 (s, 1H), 7.63(d, 1H), 7.49 (dd, 1H), 5.53 (d, 1H), 3.70 (s, 3H), 2.61-2.55 (m, 1H),1.10 (d, 3H), 0.83 (d, 3H).

Example 1632-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanamide(racemate)

70 mg (186 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate), 27.7 mg (186 μmol, 1.0 eq.) of 5-aminobenzimidazolone,26.4 mg (186 μmol) of Oxima and 28.9 μl (186 μmol) of DIC in 3.9 ml ofdimethylformamide were reacted according to General Method 5. The crudeproduct was purified by preparative HPLC (column: Chromatorex 125 mm×30mm, 10 μm, mobile phase: water/0.1% formic acid and acetonitrile/0.1%formic acid, gradient 10% acetonitrile to 90% acetonitrile) and thensubjected to basic extraction (aqueous sodium hydroxide solution/ethylacetate). Yield: 44 mg (47% of theory)

LC/MS [Method 2]: R_(t)=2.22 min; MS (ESIpos): m/z=508 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.6 (s, 1H), 10.5 (s, 1H), 10.4 (s,1H), 8.02-7.98 (m, 1H), 7.76-7.71 (m, 2H), 7.54 (s, 1H), 7.45 (d, 1H),7.09 (dd, 1H), 6.84 (d, 1H), 6.52 (s, 1H), 5.75 (dd, 1H), 3.68 (s, 3H),3.43-3.23 (m, 2H), 3.21 (s, 3H), 2.44-2.29 (m, 2H).

Example 1642-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)butanamide(racemate)

150 mg (377 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) and 65 mg (438 μmol, 1.1 eq.) of6-amino-1H-indazol-3(2H)-one were reacted according to General Method 1.The crude product was purified by flash chromatography (silica gel 50,dichloromethane/methanol mixtures). Yield: 105 mg (52% of theory)

LC/MS [Method 1]: R_(t)=0.79 min; MS (ESIpos): m/z=508 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.1 (br. s, 1H), 10.6-10.6 (m, 2H),8.01-7.98 (m, 1H), 7.86 (d, 1H), 7.75-7.72 (m, 2H), 7.55-7.51 (m, 2H),7.08 (dd, 1H), 6.53 (s, 1H), 5.79 (dd, 1H), 3.69 (s, 3H), 3.43-3.36 (m,1H), 3.31-3.26 (m, 1H), 3.21 (s, 3H), 2.46-2.34 (m, 2H).

Example 1652-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)butanamide(racemate)

225 mg (362 μmol) of tert-butyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate) were hydrolysed with TFA according to General Method 2.Yield: 205 mg (purity 92%, 100% of theory)

LC/MS [Method 1]: R_(t)=0.82 min; MS (ESIpos): m/z=522 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.7 (s, 1H), 10.2 (s, 1H), 8.02-7.97(m, 1H), 7.77 (d, 1H), 7.75-7.72 (m, 2H), 7.56 (d, 1H), 7.52 (s, 1H),7.20 (dd, 1H), 6.53 (s, 1H), 5.77 (dd, 1H), 3.69 (s, 3H), 3.44-3.37 (m,1H), 3.32 (s, 3H), 3.31-3.26 (m, 1H), 3.21 (s, 3H), 2.47-2.36 (m, 2H).

Example 1662-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(1H-indazol-5-yl)-4-methoxybutanamide(racemate)

150 mg (398 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) and 58.3 mg (438 μmol, 1.1 eq.) of 5-aminoindazole werereacted according to General Method 1. The crude product was purified bypreparative HPLC (column: Chromatorex 125 mm×30 mm, 10 μm, mobile phase:water and acetonitrile, gradient 10% acetonitrile to 90% acetonitrile).Yield: 88 mg (42% of theory)

LC/MS [Method 1]: R_(t)=0.87 min; MS (ESIpos): m/z=492 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.0 (s, 1H), 10.5 (s, 1H), 8.14 (s,1H), 8.02 (s, 1H), 8.01-7.98 (m, 1H), 7.75-7.70 (m, 2H), 7.56 (s, 1H),7.49 (s, 2H), 6.53 (s, 1H), 5.80 (dd, 1H), 3.69 (s, 3H), 3.44-3.37 (m,1H), 3.34-3.26 (m, 1H), 3.22 (s, 3H), 2.48-2.31 (m, 2H).

Example 1672-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(3-chloro-1H-indazol-5-yl)-4-methoxybutanamide(racemate)

170 mg (451 μmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoicacid (racemate) and 92.4 mg (purity 90%, 496 μmol, 1.1 eq.) of5-amino-3-chloro-1H-indazole were reacted according to General Method 1.The crude product was purified by flash chromatography (silica gel 50,cyclohexane/ethyl acetate mixtures). Yield: 113 mg (48% of theory)

LC/MS [Method 1]: R_(t)=0.97 min; MS (ESIpos): m/z=526 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.3 (s, 1H), 10.6 (s, 1H), 8.16 (s,1H), 8.02-7.98 (m, 1H), 7.76-7.70 (m, 2H), 7.55 (s, 3H), 6.53 (s, 1H),5.79 (dd, 1H), 3.70 (s, 3H), 3.45-3.37 (m, 1H), 3.31-3.26 (m, 1H), 3.22(s, 3H), 2.48-2.31 (m, 2H).

Example 1686-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-1H-indole-2-carboxylicacid (racemate)

80 mg (142 μmol) of ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-1H-indole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide at RT according toGeneral Method 3. Yield: 50 mg (66% of theory)

LC/MS [Method 1]: R_(t)=0.92 min; MS (ESIpos): m/z=535 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 11.7-11.6 (m, 1H),10.5 (s, 1H), 8.03-7.98 (m, 2H), 7.75-7.71 (m, 2H), 7.58-7.54 (m, 2H),7.21 (dd, 1H), 7.04-7.02 (m, 1H), 6.52 (s, 1H), 5.80 (dd, 1H), 3.70 (s,3H), 3.43-3.35 (m, 1H), (1H under H₂O signal), 3.22 (s, 3H), 2.46-2.36(m, 2H).

Example 1696-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-5-methoxy-1H-indole-2-carboxylicacid (racemate)

80 mg (135 μmol) of ethyl6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-5-methoxy-1H-indole-2-carboxylate(racemate) were hydrolysed with lithium hydroxide at RT according toGeneral Method 3. Yield: 63 mg (purity 90%, 74% of theory)

LC/MS [Method 1]: R_(t)=0.93 min; MS (ESIpos): m/z=565 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.7 (br. s, 1H), 11.6 (s, 1H), 9.41(s, 1H), 8.23 (s, 1H), 8.00 (d, 1H), 7.78-7.70 (m, 2H), 7.51 (s, 1H),7.19 (s, 1H), 6.99-6.97 (m, 1H), 6.57 (s, 1H), 5.79 (dd, 1H), 3.86 (s,3H), 3.69 (s, 3H), 3.45-3.35 (m, 2H), 3.24 (s, 3H), 2.44-2.31 (m, 2H).

Example 1704-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoicacid (racemate)

45 mg (0.08 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methylpentanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 28 mg (purity 90%, 62% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=498 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.89 (s, 1H), 8.22(s, 1H), 8.07 (d, 1H), 7.92 (d, 2H), 7.84 (d, 1H), 7.79 (dd, 1H), 7.74(d, 2H), 6.70 (s, 1H), 5.84 (dd, 1H), 2.32-2.22 (m, 1H), 1.93-1.82 (m,1H), 1.48-1.35 (m, 1H), 0.94 (dd, 6H).

Example 1714-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (racemate)

142 mg (purity 81%, 0.19 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 54 mg (52% of theory)

LC/MS [Method 2]: R_(t)=3.32 min; MS (ESIpos): m/z=554 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.79 (s, 1H), 10.87 (s, 1H), 8.26(s, 1H), 8.07 (d, 1H), 7.92 (d, 2H), 7.80 (dd, 1H), 7.77 (d, 1H), 7.74(d, 2H), 6.71 (s, 1H), 5.81 (dd, 1H), 4.24-4.15 (m, 1H), 4.03-3.84 (m,1H), 2.71-2.59 (m, 2H).

Example 1724-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoyl)amino]benzoicacid (racemate)

263 mg (purity 88%, 0.39 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methylpentanoyl)amino]benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 140 mg (67% of theory)

LC/MS [Method 1]: R_(t)=1.10 min; MS (ESIpos): m/z=535 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.78 (s, 1H), 10.84 (s, 1H), 7.91(d, 2H), 7.76 (d, 2H), 7.58 (dd, 1H), 7.50 (d, 1H), 7.40 (s, 1H), 7.29(d, 1H), 7.13 (t, 1H), 6.40 (s, 1H), 5.84 (dd, 1H), 3.63 (s, 3H),2.22-2.12 (m, 1H), 1.92-1.82 (m, 1H), 1.49-1.36 (m, 1H), 0.94 (t, 6H).

Example 1734-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]benzoicacid (racemate)

66 mg (0.11 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}4-methoxybutanoyl)amino]benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 31 mg (52% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=537 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.73 (s, 1H), 10.73 (s, 1H), 7.90(d, 2H), 7.76 (d, 2H), 7.57 (dd, 1H), 7.49 (d, 1H), 7.40 (s, 1H), 7.30(d, 1H), 7.13 (t, 1H), 6.39 (s, 1H), 5.74 (dd, 1H), 3.63 (s, 3H),3.42-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.20 (s, 3H), 2.45-2.34 (m, 2H).

Example 1742-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxy-N-(2-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl)butanamide(racemate)

132 mg (0.19 mmol) of tert-butyl6-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 48 mg (45% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=563 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.65 (s, 1H), 10.19 (s, 1H), 7.77(d, 1H), 7.61-7.51 (m, 2H), 7.49 (d, 1H), 7.42 (s, 1H), 7.33-7.25 (m,2H), 7.19 (dd, 1H), 7.13 (t, 1H), 6.39 (s, 1H), 5.75 (dd, 1H), 3.63 (s,3H), 3.32 (s, 3H), 3.20 (s, 3H), 2.43-2.30 (m, 2H).

Example 1752-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxy-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanamide(racemate)

76 mg (purity 82%, 0.15 mmol) of2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoicacid (racemate) and 25 mg (0.17 μmol, 1.1 eq.) of 5-aminobenzimidazolonewere reacted according to General Method 1. The crude product waspurified by preparative HPLC (Reprosil C18, water/acetonitrilegradient). Yield: 37 mg (45% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=549 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.56 (s, 1H), 10.50 (s, 1H), 10.30(s, 1H), 7.57 (dd, 1H), 7.48 (d, 1H), 7.46-7.40 (m, 2H), 7.30 (d, 1H),7.12 (t, 1H), 7.09 (dd, 1H), 6.84 (d, 1H), 6.37 (s, 1H), 5.73 (dd, 1H),3.62 (s, 3H), 3.34-3.23 (m, 2H), 3.20 (s, 3H), 2.40-2.25 (m, 2H).

Example 1764-{[2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoicacid (racemate)

195 mg (0.29 mmol) of tert-butyl4-{[2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 84 mg (50% of theory)

LC/MS [Method 1]: R_(t)=1.07 min; MS (ESIpos): m/z=591 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.75 (s, 1H), 7.91(d, 2H), 7.75 (d, 2H), 7.58 (dd, 1H), 7.46 (d, 1H), 7.40 (s, 1H), 7.30(d, 1H), 7.11 (t, 1H), 6.41 (s, 1H), 5.79 (t, 1H), 4.19-4.11 (m, 1H),4.04-3.95 (m, 1H), 3.63 (s, 3H), 2.65-2.57 (m, 2H).

Example 1774-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

67 mg (0.11 mmol) of tert-butyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. The crude product was purifiedby preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield:25 mg (41% of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=577 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.75 (s, 1H), 10.74/10.65 (2×s, 1H),7.94-7.86 (m, 2H), 7.81-7.72 (m, 2H), 7.59/7.56 (2×t, 1H), 7.50/7.48(2×d, 1H), 7.42/7.38 (2×s, 1H), 7.33-7.27 (m, 1H), 7.13/7.12 (2×t, 1H),6.38/6.37 (2×s, 1H), 5.80/5.72 (t/dd, 1H), 3.90-3.78 (m, 1H), 3.63/3.62(2×s, 3H), 3.29-3.03 (m, 2H), 2.39-2.09 (m, 2H), 1.79-1.70 (m, 1H),1.67-1.54 (m, 1H), 1.48-1.18 (m, 4H).

Example 1784-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoicacid (racemate)

249 mg (0.43 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoate(racemate) were reacted according to General Method 2. The crude productwas purified by preparative HPLC (water/acetonitrile/0.1% formic acidgradient). Yield: 145 mg (65% of theory)

LC/MS [Method 8]: R_(t)=1.19 min; MS (ESIpos): m/z=484 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.99 (br. s, 1H), 10.94 (s, 1H),8.02-7.97 (m, 1H), 7.86 (t, 1H), 7.77-7.67 (m, 3H), 6.54 (s, 1H), 5.60(dd, 1H), 3.69 (s, 3H), 3.26-2.11 (m, 2H), 0.91 (t, 3H),

¹⁹F-NMR (376.54 MHz, DMSO-d₆): δ [ppm]=−107.7.

Example 1794-({(2S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzoicacid (enantiomer 2)

Enantiomer separation of 135 mg of the racemate from Example 178 gave 36mg of the title compound Example 179 (enantiomer 2): chiral SFC:R_(t)=2.67 min; 99% ee.

Separation method (SFC): column: Chiralpak AZ-H 5 μm 250 mm×30 mm;mobile phase: 60% carbon dioxide, 40% ethanol; temperature: 40° C.; flowrate: 100 ml/min; pressure: 80 bar; UV detection: 220 nm.

Analysis: column: Chiralpak AZ-H 5μ 250 mm×4.6 mm; mobile phase: 60%carbon dioxide, 40% ethanol; flow rate: 3 ml/min; UV detection: 220 nm.

Example 1804-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoylamino)-3-fluorobenzoic acid (racemate)

125 mg (0.23 mmol) of tert-butyl4-(2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-3-fluorobenzoate(racemate) were reacted according to General Method 2. The crude productwas purified by preparative HPLC (water/acetonitrile/0.1% formic acidgradient). Yield: 57 mg (51% of theory)

LC/MS [Method 1]: R_(t)=0.94 min; MS (ESIpos): m/z=484 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.13 (br. s, 1H), 10.55 (s, 1H),8.11 (t, 1H), 8.02-7.97 (m, 1H), 7.79-7.70 (m, 4H), 7.46 (s, 1H), 6.55(s, 1H), 5.80 (dd, 1H), 3.68 (s, 3H), 2.27-2.10 (m, 2H), 0.91 (t, 3H),

¹⁹F-NMR (376.54 MHz, DMSO-d₆): δ [ppm]=−123.9.

Example 1814-({(2S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-3-fluorobenzoicacid (enantiomer 2)

Enantiomer separation of 55 mg of the racemate from Example 180 gave 27mg of the title compound Example 181 (enantiomer 2): chiral SFC:R_(t)=7.07 min; >99% ee.

Separation method (SFC): column: AD-H 5 μm 250 mm×20 mm; mobile phase:85% carbon dioxide, 15% ethanol; temperature: 40° C.; flow rate: 100ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: AD-H 5 μm 250 mm×4.6 mm; mobile phase: 80% carbondioxide, 20% ethanol; flow rate: 3 ml/min; UV detection: 220 nm.

Example 1824-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,5-difluorobenzoicacid (racemate)

179 mg (0.32 mmol) of tert-butyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,5-difluorobenzoate(racemate) were reacted according to General Method 6A. The crudeproduct was purified by preparative HPLC (water/acetonitrile/0.1% formicacid gradient). Yield: 105 mg (65% of theory)

LC/MS [Method 8]: R_(t)=1.21 min; MS (ESIpos): m/z=502 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.36 (br. s, 1H), 10.74 (s, 1H),8.08-7.97 (m, 2H), 7.77-7.68 (m, 3H), 7.45 (s, 1H), 6.55 (s, 1H),5.85-5.78 (m, 1H), 3.69 (s, 3H), 2.25-2.14 (m, 2H), 0.90 (t, 3H),

¹⁹F-NMR (376.54 MHz, DMSO-d₆): δ [ppm]=−112.6, −129.8.

Example 1834-({(2S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,5-difluorobenzoicacid (enantiomer 2)

Enantiomer separation of 100 mg of the racemate from Example 182 gave 33mg of the title compound Example 183 (enantiomer 2): chiral SFC:R_(t)=3.05 min; >99% ee.

Separation method (SFC): column: Chiralpak AZ-H 5 μ 250 mm×30 mm; mobilephase: 75% carbon dioxide, 25% ethanol; temperature: 40° C.; flow rate:100 ml/min; pressure: 100 bar; UV detection: 210 nm.

Analysis: column: Chiralpak AZ-H 5μ 250 mm×4.6 mm; mobile phase: 70%carbon dioxide, 30% ethanol; flow rate: 3 ml/min; UV detection: 220 nm.

Example 1844-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,3-difluorobenzoicacid (racemate)

80 mg (0.15 mmol) of methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,3-difluorobenzoate(racemate) were reacted according to General Method 6B. The crudeproduct was purified by preparative HPLC (water/acetonitrile/0.1% formicacid gradient). Yield: 58 mg (74% of theory)

LC/MS [1]: R_(t)=0.96 min; MS (ESIpos): m/z=502 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.40 (br. s, 1H), 10.73 (s, 1H),8.02-7.97 (m, 1H), 7.90-7.84 (m, 1H), 7.76-7.71 (m, 2H), 7.71-7.64 (m,1H), 7.45 (s, 1H), 6.55 (s, 1H), 5.78 (dd, 1H), 3.68 (s, 3H), 2.27-2.13(m, 2H), 0.91 (t, 3H),

¹⁹F-NMR (376.54 MHz, DMSO-d₆): δ [ppm]=−135.72, −147.97.

Example 1854-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,6-difluorobenzoicacid (racemate)

67 mg (0.20 mmol, 2 eq.) of caesium carbonate were added to a solutionof 53 mg (0.10 mmol) of methyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,6-difluorobenzoate(racemate) in 1.25 ml of a mixture of methanol/water (4/1), and theresulting suspension was stirred at 60° C. for 1 h. Methanol was removedat 30° C. under reduced pressure. The reaction mixture was cooled to RTand adjusted to pH 3 using aqueous hydrochloric acid (1N). The aqueousphase was extracted with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated under reducedpressure. The crude product was purified by preparative HPLC(water/acetonitrile/0.1% formic acid gradient). Yield: 11 mg (21% oftheory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=502 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.63 (br. s, 1H), 10.88 (br. s, 1H),8.00 (d, 1H), 7.76-7.71 (m, 2H), 7.47 (s, 1H), 7.40-7.28 (m, 2H), 6.54(s, 1H), 5.56 (dd, 1H), 3.69 (s, 3H), 2.24-2.11 (m, 2H), 0.89 (t, 3H).

Example 1862-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]butanamide(racemate)

65 mg (0.19 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 54 mg (0.28 mmol, 1.5 eq.) of3-(4-aminophenyl)-1,2,4-thiadiazol-5(4H)-one were reacted according toGeneral Method 7. The crude product was purified by preparative HPLC(water/acetonitrile/0.1% formic acid gradient). Yield: 45 mg (46% oftheory)

LC/MS [Method 8]: Rt=1.25 min; MS (ESIpos): m/z=521 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.31 (br. s, 1H), 10.78 (s, 1H),8.02-7.98 (m, 1H), 7.94-7.89 (m, 2H), 7.80-7.71 (m, 4H), 7.50 (s, 1H),6.54 (s, 1H), 5.64 (dd, 1H), 3.69 (s, 3H), 2.26-2.10 (m, 2H), 0.91 (t,3H).

Example 187(2S)-2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)phenyl]butanamide(enantiomer 2)

Enantiomer separation of 40 mg of the racemate from Example 186 gave 10mg of the title compound Example 187 (enantiomer 2): Chiral HPLC:R_(t)=6.83 min; >99% ee.

Separation method (HPLC): column: Chiralpak IB 5 μm 250 mm×20 mm; mobilephase: 50% hexane, 50% 2-propanol; temperature: 35° C.; flow rate: 20ml/min; UV detection: 220 nm.

Analysis: column: Chiralcel OD-H 5 μm 250 mm×4.6 mm; mobile phase: 50%hexane, 50% 2-propanol; flow rate: 1 ml/min; temperature: 30° C.; UVdetection: 220 nm.

Example 1882-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]butanamide(racemate)

36 mg (0.10 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 30 mg (0.16 mmol, 1.5 eq.) of3-(4-aminophenyl)-1,2,4-oxadiazole-5(4H)-thione were reacted accordingto General Method 7. The crude product was purified by preparative HPLC(water/acetonitrile/0.1% formic acid gradient). Yield: 21 mg (38% oftheory)

LC/MS [Method 8]: Rt=1.26 min; MS (ESIneg): m/z=520 (M−H)⁻,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.85 (s, 1H), 8.02-7.97 (m, 1H),7.89-7.80 (m, 4H), 7.76-7.71 (m, 2H), 7.50 (s, 1H), 6.54 (s, 1H), 5.64(dd, 1H), 3.69 (s, 3H), 2.26-2.11 (m, 2H), 0.91 (t, 3H).

Example 1892-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(1,3-oxazol-2-yl)phenyl]butanamide(racemate)

100 mg (0.29 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of4-(1,3-oxazol-2-yl)aniline were reacted according to General Method 7.The crude product was purified by normal phase chromatography (mobilephase: dichloromethane/methanol 1-10% mixtures). Yield: 89 mg (63% oftheory)

LC/MS [Method 1]: Rt=1.04 min; MS (ESIpos): m/z=489 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.76 (s, 1H), 8.18 (d, 1H), 8.00 (d,1H), 7.98-7.93 (m, 2H), 7.83-7.78 (m, 2H), 7.76-7.71 (m, 2H), 7.51 (s,1H), 7.35 (d, 1H), 6.54 (s, 1H), 5.65 (dd, 1H), 3.69 (s, 3H), 2.26-2.10(m, 2H), 0.91 (t, 3H).

Example 1902-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(1,2,4-oxadiazol-3-yl)phenyl]butanamide(racemate)

100 mg (0.29 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 73 mg (0.43 mmol, 1.5 eq.) of4-(1,2,4-oxadiazol-3-yl)aniline were reacted according to General Method7. The crude product was purified by normal phase chromatography (mobilephase: dichloromethane/methanol 2-5% mixtures) and subsequently bypreparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield:81 mg (55% of theory)

LC/MS [Method 1]: Rt=0.95 min; MS (ESIpos): m/z=490 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.85 (s, 1H), 9.30 (s, 1H),8.03-7.97 (m, 3H), 7.89-7.84 (m, 2H), 7.76-7.71 (m, 2H), 7.51 (s, 1H),6.55 (s, 1H), 5.65 (dd, 1H), 3.70 (s, 3H), 2.27-2.12 (m, 2H), 0.92 (t,3H).

Example 1912-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]butanamide(racemate)

100 mg (0.29 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 76 mg (0.43 mmol, 1.5 eq.) of4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline were reacted according toGeneral Method 7. The crude product was purified by normal phasechromatography (mobile phase: dichloromethane/methanol 1-10% mixtures).Yield: 144 mg (99% of theory)

LC/MS [Method 1]: Rt=0.98 min; MS (ESIpos): m/z=504 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=10.83 (s, 1H), 8.02-7.97 (m, 1H),7.97-7.91 (m, 2H), 7.88-7.82 (m, 2H), 7.76-7.71 (m, 2H), 7.50 (s, 1H),6.54 (s, 1H), 5.65 (dd, 1H), 3.69 (s, 3H), 2.56 (s, 3H), 2.27-2.11 (m,2H), 0.92 (t, 3H).

Example 192 Methyl3-{5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-4H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoate(racemate)

87 mg (0.25 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 88 mg (0.28 mmol, 1.1 eq.) of methyl3-[5-(4-aminophenyl)-4H-1,2,4-triazol-3-yl]-2,2,3,3-tetrafluoropropanoatewere reacted according to General Method 1. The crude product waspurified by preparative HPLC (Reprosil C18, water/acetonitrilegradient). Yield: 96 mg (purity 94%, 56% of theory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=647 (M+H)⁺.

Example 1933-{5-[4-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-4H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoicacid (racemate)

96 mg (purity 94%, 0.14 mmol) of methyl3-{5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-4H-1,2,4-triazol-3-yl}-2,2,3,3-tetrafluoropropanoate(racemate) were hydrolysed with lithium hydroxide according to GeneralMethod 3. The crude product was purified by preparative HPLC (ReprosilC18, water/acetonitrile gradient). Yield: 28 mg (32% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=633 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=15.01 (br. s, 1H), 10.77 (s, 1H),8.03-7.94 (m, 3H), 7.82 (d, 2H), 7.77-7.71 (m, 2H), 7.51 (s, 1H), 6.55(s, 1H), 5.65 (dd, 1H), 3.70 (s, 3H), 2.31-2.10 (m, 2H), 0.92 (t, 3H).

Example 1942-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(4-fluoro-3-oxo-2,3-dihydro-1H-indazol-6-yl)butanamide(racemate)

100 mg (0.28 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 51 mg (0.31 mmol, 1.1 eq.) of6-amino-4-fluoro-1,2-dihydro-3H-indazol-3-one were reacted according toGeneral Method 6. The crude product was purified by preparative HPLC(Reprosil C18, water/acetonitrile gradient). Yield: 6 mg (4% of theory)

LC/MS [Method 1]: R_(t)=0.86 min; MS (ESIpos): m/z=496 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=11.63 (br. s, 1H), 10.77 (br. s, 1H),10.66 (s, 1H), 8.00 (d, 1H), 7.78-7.69 (m, 2H), 7.60 (s, 1H), 7.51 (s,1H), 6.87 (d, 1H), 6.56 (s, 1H), 5.62 (dd, 1H), 3.70 (s, 3H), 2.25-2.08(m, 2H), 0.91 (t, 3H).

Example 1952-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-[3-(trifluoromethyl)-1H-indazol-6-yl]butanamide(racemate)

82 mg (0.23 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 51 mg (0.25 mmol, 1.1 eq.) of3-(trifluoromethyl)-1H-indazole-6-amine were reacted according toGeneral Method 6. The crude product was purified by preparative HPLC(Reprosil C18, water/acetonitrile gradient). Yield: 30 mg (25% oftheory)

LC/MS [Method 1]: R_(t)=1.08 min; MS (ESIpos): m/z=530 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.83 (s, 1H), 10.81 (s, 1H), 8.28(s, 1H), 8.00 (d, 1H), 7.79-7.71 (m, 3H), 7.53 (s, 1H), 7.39 (dd, 1H),6.56 (s, 1H), 5.67 (dd, 1H), 3.70 (s, 3H), 2.27-2.11 (m, 2H), 0.92 (t,3H).

Example 1962-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(3-chloro-1H-indazol-5-yl)butanamide(racemate)

In two batches, a total of 242 mg (0.68 mmol) of2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoicacid (racemate) and 404 mg (purity 31%, 0.75 mmol, 1.1 eq.) of3-chloro-1H-indazole-5-amine were reacted according to General Method 1.The combined crude products were purified by repeated preparative HPLC(Reprosil C18, water/acetonitrile gradient). Yield: 18 mg (purity 94%,13% of theory) of the title compound Example 196 and 65 mg (55% oftheory) of the title compound Example 197, which was isolated as aby-product due to the starting material 3-chloro-1H-indazole-5-amineemployed being contaminated with 1H-indazole-5-amine.

LC/MS [Method 1]: R_(t)=1.01 min; MS (ESIpos): m/z=496 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.25 (s, 1H), 10.64 (s, 1H), 8.16(s, 1H), 8.00 (d, 1H), 7.77-7.70 (m, 2H), 7.59-7.49 (m, 3H), 6.55 (s,1H), 5.66 (dd, 1H), 3.70 (s, 3H), 2.28-2.09 (m, 2H), 0.92 (t, 3H).

Example 1972-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-N-(1H-indazol-5-yl)butanamide(racemate)

The title compound Example 197 was isolated as a by-product in thepreparation of the title compound Example 196. Yield: 65 mg (55% oftheory)

LC/MS [Method 1]: R_(t)=0.90 min; MS (ESIpos): m/z=462 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=13.00 (s, 1H), 10.50 (s, 1H), 8.15(s, 1H), 8.05-7.96 (m, 2H), 7.77-7.70 (m, 2H), 7.55 (s, 1H), 7.73-7.45(m, 2H), 6.54 (s, 1H), 5.68 (dd, 1H), 3.69 (s, 3H), 2.26-2.08 (m, 2H),0.92 (t, 3H).

Example 1984-({2-[4-(5-Chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoyl}amino)benzoicacid (racemate)

329 mg (537 μmol) of ethyl4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-dioxidotetrahydro-2H-thiopyran-4-yl)propanoyl}amino)benzoate(racemate) in 19.4 ml of ethanol/water (2.6/1) were reacted with 893 mg(2.74 mmol) of caesium carbonate according to General Method 6C, givingthe title compound after preparative HPLC [column: Chromatorex C18, 10μm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient(0 to 3 min 10% acetonitrile to 35 min 90% acetonitrile and a further 3min 90% acetonitrile)]. Yield: 136 mg (43% of theory)

LC/MS [Method 1]: R_(t)=0.89 min; MS (ESIpos): m/z=584 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.8 (br. s, 1H), 10.8 (s, 1H), 8.01(d, 1H), 7.92 (d, 2H), 7.77-7.71 (m, 4H), 7.51 (s, 1H), 6.56 (s, 1H),5.85 (dd, 1H), 3.71 (s, 3H), 3.14-2.96 (m, 4H), 2.37-2.27 (m, 1H),2.15-2.03 (m, 3H), 1.81-1.65 (m, 2H), 1.55-1.43 (m, 1H).

Example 1994-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2,9-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

315 mg (0.49 mmol) of ethyl4-[(2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoate(mixture of enantiomerically pure diastereomers 1 and 2) in 6.5 ml ofethanol/water (4/1) were hydrolyzed with 322 mg (0.99 mmol, 2.0 eq.) ofcaesium carbonate according to General Method 4. The crude product waspurified by preparative HPLC (Reprosil C18, water/acetonitrilegradient). Yield: 111 mg (39% of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=577 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.76 (s, 1H), 10.74/10.65 (2×s, 1H),7.94-7.86 (m, 2H), 7.81-7.72 (m, 2H), 7.59/7.57 (2×t, 1H), 7.50/7.48(2×d, 1H), 7.42/7.38 (2×s, 1H), 7.33-7.27 (m, 1H), 7.13/7.12 (2×t, 1H),6.38/6.37 (2×s, 1H), 5.80/5.72 (t/dd, 1H), 3.90-3.78 (m, 1H), 3.63/3.62(2×s, 3H), 3.29-3.03 (m, 2H), 2.39-2.09 (m, 2H), 1.79-1.70 (m, 1H),1.67-1.54 (m, 1H), 1.48-1.18 (m, 4H).

Example 2004-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2,9-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (enantiomerically pure diastereomer 1)

Diastereomer separation of the compound from Example 199 to give thetitle compound can be carried out by SFC on a chiral phase (for exampleDaicel Chiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel ChiralpakIF 5 μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) withcarbon dioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2014-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2,9-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (enantiomerically pure diastereomer 2)

Diastereomer separation of the compound from Example 199 to give thetitle compound can be carried out by SFC on a chiral phase (for exampleDaicel Chiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel ChiralpakIF 5 μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) withcarbon dioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2024-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (mixture of enantiomerically pure diastereomers 1 and 2)

364 mg (0.61 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate(mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysedwith TFA according to General Method 2. The crude product was purifiedby preparative flash chromatography (silica gel 50, eluent:dichloromethane/methanol gradient). Yield: 264 mg (76% of theory)

LC/MS [Method 1]: R_(t)=1.05 min; MS (ESIpos): m/z=540 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.75 (s, 1H), 10.78 (s, 1H), 8.20(d, 1H), 8.06 (dd, 1H), 7.94-7.87 (m, 2H), 7.84-7.71 (m, 4H), 6.65 (s,1H), 5.81 (br. s, 1H), 3.89-3.77 (m, 1H), 3.26-3.01 (m, 2H), 2.47-2.15(m, 2H), 1.80-1.70 (m, 1H), 1.65-1.55 (m, 1H), 1.47-1.21 (m, 4H).

Example 2034-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 1)

Diastereomer separation of the compound from Example 202 to give thetitle compound can be carried out by SFC on a chiral phase (for exampleDaicel Chiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel ChiralpakIF 5 μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) withcarbon dioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2044-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoicacid (enantiomerically pure diastereomer 2)

Diastereomer separation of the compound from Example 202 to give thetitle compound can be carried out by SFC on a chiral phase (for exampleDaicel Chiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel ChiralpakIF 5 μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) withcarbon dioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2054-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-benzoicacid (racemate)

438 mg (0.76 mmol) of tert-butyl4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate(racemate) were hydrolysed with TFA according to General Method 2. Thecrude product was purified by preparative HPLC (Reprosil C18,water/acetonitrile gradient). Yield: 123 mg (32% of theory)

LC/MS [Method 1]: R_(t)=0.96 min; MS (ESIpos): m/z=500 (M+H)⁺,

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=12.77 (br. s, 1H), 10.82 (s, 1H),8.22 (s, 1H), 8.07 (d, 1H), 7.91 (d, 2H), 7.84-7.77 (m, 2H), 7.75 (d,2H), 6.67 (s, 1H), 5.77 (br. s, 1H), 3.45-3.38 (m, 1H), 3.30-3.22 (m,1H), 3.19 (s, 3H), 2.46-2.39 (m, 2H).

Example 2064-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-benzoicacid (enantiomer 1)

Enantiomer separation of the compound from Example 205 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2074-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-benzoicacid (enantiomer 2)

Enantiomer separation of the compound from Example 205 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2084-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (enantiomer 1)

Enantiomer separation of the compound from Example 171 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2094-({2-[5-Chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-(trifluoromethoxy)butanoyl}amino)benzoicacid (enantiomer 2)

Enantiomer separation of the compound from Example 171 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2104-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]benzoicacid (enantiomer 1)

Enantiomer separation of the compound from Example 173 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2114-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoyl)amino]benzoicacid (enantiomer 2)

Enantiomer separation of the compound from Example 173 to the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2124-{[2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoicacid (enantiomer 1)

Enantiomer separation of the compound from Example 176 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2134-{[2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoyl]amino}benzoicacid (enantiomer 2)

Enantiomer separation of the compound from Example 176 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2144-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (enantiomerically pure diastereomer 1)

Enantiomer separation of the compound from Example 177 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

Example 2154-[(2-{4-[5-Chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-3-[(2R)-tetrahydro-2H-pyran-2-yl]propanoyl)amino]benzoicacid (enantiomerically pure diastereomer 2)

Enantiomer separation of the compound from Example 177 to give the titlecompound can be carried out by SFC on a chiral phase (for example DaicelChiralpak AD-H 5 μm, Daicel Chiralpak AZ-H 5 μm, Daicel Chiralpak IF 5μm, Daicel Chiralpak IC 5 μm or Daicel Chiralpak OJ-H 5 μm) with carbondioxide/ethanol or carbon dioxide/2-propanol mixtures as eluents.

B) ASSESSMENT OF PHYSIOLOGICAL EFFICACY

The suitability of the compounds according to the invention for treatingthromboembolic disorders can be demonstrated in the following assaysystems:

a) Test Descriptions (In Vitro)

a.1) Measurement of FXIa Inhibition

To determine the factor XIa inhibition of the substances according tothe invention, a biochemical test system is used which utilizes thereaction of a peptidic factor XIa substrate to determine the enzymaticactivity of human factor XIa. Here, factor XIa cleaves from the pepticfactor XIa substrate the C-terminal aminomethylcoumarin (AMC), thefluorescence of which is measured. The determinations are carried out inmicrotitre plates.

Test substances are dissolved in dimethyl sulphoxide and seriallydiluted in dimethyl sulphoxide (3000 μM to 0.0078 μM; resulting finalconcentrations in the test: 50 μM to 0.00013 μM). In each case 1 μl ofthe diluted substance solutions are placed into the wells of whitemicrotitre plates from Greiner (384 wells). 20 μl of assay buffer (50 mMof Tris/HCl pH 7.4; 100 mM of sodium chloride solution; 5 mM of calciumchloride solution; 0.1% of bovine serum albumin) and 20 μl of factor XIafrom Kordia (0.45 nM in assay buffer) are then added successively. After15 min of incubation, the enzyme reaction is started by addition of 20μl of the factor XIa substrate Boc-Glu(OBzl)-Ala-Arg-AMC dissolved inassay buffer (10 μM in assay buffer) from Bachem, the mixture isincubated at room temperature (22° C.) for 30 min and fluorescence isthen measured (excitation: 360 nm, emission: 460 nm). The measuredemissions of the test batches with test substance are compared to thoseof control batches without test substance (only dimethyl sulphoxideinstead of test substance in dimethyl sulphoxide), and the IC₅₀ valuesare calculated from the concentration/activity relationships. Activitydata from this test are listed in Table A below:

TABLE A Example No. IC₅₀ [nM] Example No. IC₅₀ [nM] 1 53 2 260 3 430 4240 5 150 6 440 7 82 8 110 9 170 10 730 11 750 12 500 13 600 14 330 15430 16 910 17 960 18 840 19 59 20 27000 21 26 22 1700 23 150 24 240 25220 26 7.6 27 42 28 49 29 36 30 50 31 24000 32 65 33 33 34 74 35 27 3617000 37 14 38 230 39 1100 40 35 41 54 42 14 43 40 44 140 45 13 46 330047 9.8 48 42 49 43 50 470 51 500 52 700 53 630 54 3500 55 5.9 56 3400 572.0 58 3.9 59 950 60 1.6 61 4.8 62 290 63 9.1 64 4000 65 4.7 66 4.7 671700 68 1.8 69 3.5 70 24 71 32 72 34 73 6.2 74 17 75 4.3 76 1.6 77 200078 1.3 79 3.2 80 4000 81 0.7 82 18 83 5.8 84 4.4 85 1900 86 2.4 87 2.888 1.3 89 75 90 8.5 91 470 92 3.2 93 4.0 94 5.5 95 520 96 2.4 97 4.2 98890 99 920 100 1.5 101 1.3 102 660 103 0.5 104 7.3 105 1.4 106 2.3 1075.3 108 6.4 109 31 110 9.2 111 34 112 32 113 4.3 114 600 115 3.0 116 2.3117 1.9 118 53 119 28 120 46 121 17 122 52 123 63 124 170 125 3.6 1267.1 127 10 128 11 129 24 130 50 131 81 132 2.0 133 130 134 0.3 135 2.7136 1.6 137 1200 138 1.0 139 2.5 140 3.8 141 190 142 3.9 143 0.6 144 98145 17 146 130 147 14 148 59 149 5.0 150 4.7 151 14 152 5.4 153 1100 1542.4 155 2.0 156 600 157 0.8 158 22 159 18 160 120 161 2000 162 1100 1636.0 164 2.2 165 11 166 6.8 167 28 168 3.9 169 160 170 49 171 5.2 172 21173 2.6 174 19 175 15 176 4.5 177 3.4 178 3.0 179 2.3 180 13 181 11 18231 183 14 184 10 185 5.5 186 5.3 187 2.8 188 4.5 189 66 190 80 191 49192 3.0 193 2.6 194 6.8 195 150 196 110 197 17 198 12 199 1.3 202 2.9205 4.0a.2) Determination of the Selectivity

To demonstrate the selectivity of the substances with respect to FXIainhibition, the test substances are examined for their inhibition ofother human serin proteases, such as factor Xa, trypsin and plasmin Todetermine the enzymatic activity of factor Xa (1.3 nmol/l from Kordia),trypsin (83 mU/ml from Sigma) and plasmin (0.1 μg/ml from Kordia), theseenzymes are dissolved (50 mmol/l of Tris buffer[C,C,C-tris(hydroxymethyl)aminomethane], 100 mmol/1 of sodium chloride,0.1% BSA [bovine serum albumin], 5 mmol/1 of calcium chloride, pH 7.4)and incubated for 15 min with test substance in various concentrationsin dimethyl sulphoxide and also with dimethyl sulphoxide without testsubstance. The enzymatic reaction is then started by addition of theappropriate substrates (5 μmol/l of Boc-Ile-Glu-Gly-Arg-AMC from Bachemfor factor Xa and trypsin, 50 μmol/l of MeOSuc-Ala-Phe-Lys-AMC fromBachem for plasmin) After an incubation time of 30 min at 22° C.,fluorescence is measured (excitation: 360 nm, emission: 460 nm). Themeasured emissions of the test batches with test substance are comparedto the control batches without test substance (only dimethyl sulphoxideinstead of test substance in dimethyl sulphoxide), and the IC₅₀ valuesare calculated from the concentration/activity relationships.

a.3) Thrombin Generation Assay (Thrombogram)

The effect of the test substances on the thrombogram (thrombingeneration assay according to Hemker) is determined in vitro in humanplasma (Octaplas® from Octapharma).

In the thrombin generation assay according to Hemker, the activity ofthrombin in coagulating plasma is determined by measuring thefluorescent cleavage products of the substrate I-1140(Z-Gly-Gly-Arg-AMC, Bachem). The reactions are carried out in thepresence of varying concentrations of test substance or thecorresponding solvent. To start the reaction, reagents fromThrombinoscope (30 pM or 0.1 pM recombinant tissue factor, 24 μMphospholipids in HEPES) are used. Moreover, a thrombin calibrator fromThrombinoscope is used whose amidolytic activity is required forcalculating the thrombin activity in a sample containing an unknownamount of thrombin. The test is carried out according to thespecifications of the manufacturer (Thrombinoscope BV): 4 μl of testsubstance or of the solvent, 76 μl of plasma and 20 μl of PPP reagent orthrombin calibrator are incubated at 37° C. for 5 min. After addition of20 μl of 2.5 mM thrombin substrate in 20 mM HEPES, 60 mg/ml of BSA, 102mM of calcium chloride, the thrombin generation is measured every 20 sover a period of 120 min. Measurement is carried out using a fluorometer(Fluoroskan Ascent) from Thermo Electron fitted with a 390/460 nM filterpair and a dispenser.

Using the Thrombinoscope software, the thrombogram is calculated andrepresented graphically. The following parameters are calculated: lagtime, time to peak, peak, ETP (endogenous thrombin potential) and starttail.

a.4) Determination of the Anticoagulatory Activity

The anticoagulatory activity of the test substances is determined invitro in human plasma and rat plasma. To this end, blood is drawn off ina mixing ratio of sodium citrate/blood of 1/9 using a 0.11 molar sodiumcitrate solution as receiver. Immediately after the blood has been drawnoff, it is mixed thoroughly and centrifuged at about 4000 g for 15minutes. The supernatant is pipetted off.

The prothrombin time (PT, synonyms: thromboplastin time, quick test) isdetermined in the presence of varying concentrations of test substanceor the corresponding solvent using a commercial test kit (Neoplastin®from Boehringer Mannheim or Hemoliance® RecombiPlastin fromInstrumentation Laboratory). The test compounds are incubated with theplasma at 37° C. for 3 minutes. Coagulation is then started by additionof thromboplastin, and the time when coagulation occurs is determined.The concentration of test substance which effects a doubling of theprothrombin time is determined.

The activated partial thromboplastin time (APTT) is determined in thepresence of varying concentrations of test substance or thecorresponding solvent using a commercial test kit (PTT reagent fromRoche). The test compounds are incubated with the plasma and the PTTreagent (Cephalin, Kaolin) at 37° C. for 3 minutes. Coagulation is thenstarted by addition of 25 mM calcium chloride, and the time whencoagulation occurs is determined. The concentration of test substancewhich effects an extension by 50% or a doubling of the APTT isdetermined.

a.5) Determination of the Plasma Kallikrein Activity

To determine the plasma kallikrein inhibition of the substancesaccording to the invention, a biochemical test system is used whichutilizes the reaction of a peptidic plasma kallikrein substrate todetermine the enzymatic activity of human plasma kallikrein. Here,plasma kallikrein cleaves from the peptic plasma kallikrein substratethe C-terminal aminomethylcoumarin (AMC), the fluorescence of which ismeasured. The determinations are carried out in microtitre plates.

Test substances are dissolved in dimethyl sulphoxide and seriallydiluted in dimethyl sulphoxide (3000 μM to 0.0078 μM; resulting finalconcentrations in the test: 50 μM to 0.00013 μM). In each case 1 μl ofthe diluted substance solutions are placed into the wells of whitemicrotitre plates from Greiner (384 wells). 20 μl of assay buffer (50 mMTris/HCl pH 7.4; 100 mM sodium chloride solution; 5 mM of calciumchloride solution; 0.1% of bovine serum albumin) and 20 μl of plasmakallikrein from Kordia (0.6 nM in assay buffer) are then addedsuccessively. After 15 min of incubation, the enzyme reaction is startedby addition of 20 μl of the substrate H-Pro-Phe-Arg-AMC dissolved inassay buffer (10 μl in assay buffer) from Bachem, the mixture isincubated at room temperature (22° C.) for 30 min and fluorescence isthen measured (excitation: 360 nm, emission: 460 nm). The measuredemissions of the test batches with test substance are compared to thoseof control batches without test substance (only dimethyl sulphoxideinstead of test substance in dimethyl sulphoxide), and the IC₅₀ valuesare calculated from the concentration/activity relationships.

TABLE B Example No. IC₅₀ [nM] Example No. IC₅₀ [nM] 1 600 3 650 4 590 5330 6 640 7 220 8 490 9 840 17 630 18 490 21 120 22 595 23 520 26 67 27780 28 570 29 350 30 620 32 800 33 320 34 310 35 510 37 275 40 550 411600 42 110 43 230 44 140 45 200 47 150 55 31 57 17 58 46 60 15.5 61 2963 67 65 25 66 31 68 14.5 69 11 70 16 71 17 72 29 73 16 74 10 75 28 7612 78 4.1 79 15 81 7.6 82 45 83 15 84 40 86 16.5 87 14 88 7.9 89 850 9054 92 35 93 18 94 48 96 19 97 26 100 15 101 19 103 5.9 104 67 105 13 10621 107 56 108 59 109 220 110 78 111 220 112 200 113 39 115 16 116 11 11712 118 210 119 200 121 220 122 700 123 1100 125 23 126 64 127 160 128180 129 390 130 1300 132 18 134 5.8 135 19 136 9.4 138 6.5 139 9.4 14032 141 1600 142 18 143 4.6 144 1000 145 98 146 1500 147 70 148 430 14927 150 18 151 110 152 75 154 45 155 10 157 5.2 158 29 159 16 160 240 1611500 162 250 163 3.6 164 1.9 165 8.2 166 6.3 167 8.4 168 3.1 169 54 170670 171 89 172 360 173 54 174 28 175 20 176 58 177 120 178 33 179 24 18078 181 45 182 130 183 62 184 110 185 40 186 31 187 14 188 31 189 63 19035 191 35 192 61 193 46 194 6.3 195 59 196 21 197 10 198 39 199 34 20282 205 68a.6) Determination of Endothel Integrity

The activity of the compounds according to the invention ischaracterized by means of an in vitro permeability assay on “humanumbilical venous cells” (HUVEC). Using the EOS apparatus (EC IS:Electric Cell-substrate Impedance Sensing; Applied Biophysics Inc; Troy,N.Y.), it is possible to measure continuously variations in thetransendothelial electrical resistance (TEER) across an endothelial cellmonolayer plated over gold electrodes. HUVECs are shown on a 96-wellsensor electrode plate (96W1 E, Ibidi GmbH, Martinsried, Germany).Hyperpermeability of the confluent cell monolayer formed is induced bystimulation with kininogen, prekallikrein and factor XII (100 nM each).The compounds according to the invention are added prior to the additionof the substances indicated above. The customary concentrations of thecompounds are 1×10⁻¹⁰ to 1×10⁻⁶ M.

a.7) Determination of the In Vitro Permeability of Endothelial Cells

In a further hyperpermeability model, the activity of the substances onthe modulation of macromolecular permeability is determined HUVECs areshown on a fibronectin-coated Transwell filter membrane (24-well plates,6.5 mm insert with 0.4 μM polycarbonate membrane; Costar #3413). Thefilter membrane separates the upper from the lower cell culture chamber,with the confluent endothelial cell layer on the floor of the upper cellculture chamber. 250 g/ml of 40 kDa FITC dextan (Invitrogen, D1844) isadded to the medium of the upper chamber. Hyperpermeability of themonolayer formed is induced by stimulation with kininogen, prekallikreinand factor XII (100 nM each). Every 30 min, medium samples are removedfrom the lower chamber and relative fluorescence as a parameter forchanges in macromolecular permeability as a function of time isdetermined using a fluorimeter. The compounds according to the inventionare added prior to the addition of the substances indicated above. Thecustomary concentrations of the compounds are 1×10⁻¹⁰ to 1×10⁻⁶ M.

b) Determination of Antithrombotic Activity (In Vivo)

b.1) Arterial Thrombosis Model (Iron(II) Chloride-Induced Thrombosis) inCombination with Ear Bleeding Time in Rabbits

The antithrombotic activity of the FXIa inhibitors is tested in anarterial thrombosis model. Thrombus formation is triggered here bycausing chemical injury to a region in the carotid artery in rabbits.Simultaneously, the ear bleeding time is determined

Male rabbits (Crl:KBL (NZW)BR, Charles River) receiving a normal dietand having a body weight of 2.2-2.5 kg are anaesthetized byintramuscular administration of xylazine and ketamine (Rompun, Bayer, 5mg/kg and Ketavet, Pharmacia & Upjohn GmbH, 40 mg/kg body weight).Anaesthesia is furthermore maintained by intravenous administration ofthe same preparations (bolus: continuous infusion) via the rightauricular vein.

The right carotid artery is exposed and the tissue injury is then causedby wrapping a piece of filter paper (10 mm×10 mm) on a Parafilm® strip(25 mm×12 mm) around the carotid artery without disturbing the bloodflow. The filter paper contains 100 μl of a 13% strength solution ofiron(II) chloride (Sigma) in water. After 5 min, the filter paper isremoved and the vessel is rinsed twice with aqueous 0.9% strength sodiumchloride solution. 30 min after the injury the injured region of thecarotid artery is extracted surgically and any thrombotic material isremoved and weighed.

The test substances are administered either intravenously to theanaesthetized animals via the femoral vein or orally to the awakeanimals via gavage, in each case 5 min and 2 h, respectively, before theinjury.

Ear bleeding time is determined 2 min after injury to the carotidartery. To this end, the left ear is shaved and a defined 3-mm-longincision (blade Art. Number 10-150-10, Martin, Tuttlingen, Germany) ismade parallel to the longitudinal axis of the ear. Care is taken herenot to damage any visible vessels. Any blood that extravasates is takenup in 15 second intervals using accurately weighed filter paper pieces,without touching the wound directly. Bleeding time is calculated as thetime from making the incision to the point in time where no more bloodcan be detected on the filter paper. The volume of the extravasatedblood is calculated after weighing of the filter paper pieces.

c) Determination of the Effect on Extravasation/Oedema Formation and/orNeovascularization in the Eye (In Vivo)

c.1) Test of the Efficacy of Substances in the Laser-Induced ChoroidalNeovascularization Model

This study serves to investigate the efficacy of a test substance onreduction of extravasation/oedema formation and/or choroidalneovascularization in the rat model of laser-induced choroidalneovascularization.

To this end, pigmented rats of the Brown-Norway strain not showing anysigns of ophthalmic disorders are selected and randomized into treatmentgroups. On day 0, the animals are anaesthetized by intraperitonealinjection (15 mg/kg xylazine and 80 mg/kg ketamine). Followinginstillation of a drop of a 0.5% strength tropicamide solution to dilatethe pupils, choroidal neovascularization is triggered on six definedlocations around the optical nerve using a 532 nm argon laserphotocoagulator (diameter 50-75 μm, intensity 150 mW, duration 100 ms).The test substance and the appropriate vehicle (e.g. PBS, isotonicsaline) are administered either systemically by the oral orintraperitonal route, or topically to the eye by repeated administrationas eye drops or intravitreal injection. The body weight of all theanimals is determined before the start of the study, and then dailyduring the study.

On day 21, an angiography is carried out using a fluorescence funduscamera (e.g. Kowe, HRA). Under anaesthesia and after another pupildilation, a 10% strength sodium fluorescein dye is injectedsubcutaneously (s.c.). 2-10 min later, pictures of the eye backgroundare taken. The degree of extravasation/the oedema, represented by theleakage of fluorescein, is assessed by two to three blinded observersand classified into degrees of severity from 0 (no extravasation) to 3(strong colouration exceeding the actual lesion).

The animals are sacrificed on day 23, after which the eyes are removedand fixated in 4% strength paraformaldehyde solution for one hour atroom temperature. After one washing, the retina is carefully peeled offand the sclera-choroidea complex is stained using an FITC isolectin B4antibody and then applied flat to a microscope slide. The preparationsobtained in this manner are evaluated using a fluorescence microscope(Apotom, Zeiss) at an excitation wavelength of 488 nm. The area orvolume of the choroidal neovascularization (in μm² and μm³,respectively) is calculated by morphometric analysis using Axiovision4.6 software.

c.2) Test of the Efficacy of Substances in the Oxygen-InducedRetinopathy Model

It has been shown that oxygen-induced retinopathy is a useful animalmodel for the study of pathological retinal angiogenesis. This model isbased on the observation that hyperoxia during early postnataldevelopment in the retina causes arrest or delay of the growth of normalretinal blood vessels. When, after a 7-day hyperoxia phase, the animalsare returned to normoxic room air, this is equivalent to relativehypoxia since the retina is missing the normal vessels which arerequired to ensure adequate supply of the neural tissue under normoxicconditions. The ischaemic situation caused in this manner results in anabnormal neovascularization which has some similarities withpathophysiological neovascularization in eye disorders such as wet AMD.In addition, the neovascularization caused is highly reproducible,quantifiable and an important parameter for examining the diseasemechanisms and possible treatments for various forms of retinaldisorders.

The aim of this study is to examine the efficacy of daily systemicallyadministered doses of the test compound on the growth of retinal vesselsin the oxygen-induced retinopathy model. Neonates of C57Bl/6 mice andtheir mothers are exposed to hyperoxia (70% oxygen) on postnatal day 7(PD7) for 5 days. From PD12, the mice are kept under normoxic conditions(room air, 21% oxygen) until PD17. From day 12 to day 17, the mice aretreated daily with the test substance or the corresponding vehicle. Onday 17, all mice are anaesthetized with isoflurane and then sacrificedby cervical fracture. The eyes are removed and fixated in 4% Formalin.After washing in phosphate-buffered saline, the retina is excised, aflat preparation thereof is produced and this is stained with isolectinB4 antibody. Quantification of neovascularization is carried out using aZeiss ApoTome.

C) WORKING EXAMPLES FOR PHARMACEUTICAL COMPOSITIONS

The substances according to the invention can be converted topharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of maize starch, 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF,Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm

Production:

The mixture of the compound of Example 1, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Afterdrying, the granules are mixed with the magnesium stearate for 5 min.This mixture is pressed with a conventional tableting press (for tabletdimensions see above).

Oral Suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water.

A single dose of 100 mg of the compound according to the inventioncorresponds to 10 ml of oral suspension.

Production:

The Rhodigel is suspended in ethanol, and the compound of Example 1 isadded to the suspension. The water is added while stirring. The mixtureis stirred for approx. 6 h until the Rhodigel has finished swelling.

Solution or Suspension for Topical Administration to the Eye (EyeDrops):

A sterile pharmaceutical preparation for topical administration to theeye can be prepared by reconstituting a lyophilisate of the compoundaccording to the invention in sterile saline. Suitable preservatives forsuch a solution or suspension are, for example, benzalkonium chloride,thiomersal or phenylmercury nitrate in a concentration range of from0.001 to 1 percent by weight.

The invention claimed is:
 1. A compound of the formula

in which R¹ represents a group of the formula

where * is the point of attachment to the oxopyridine ring, R⁶represents bromine, chlorine, fluorine, methyl, difluoromethyl,trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy, R⁷represents bromine, chlorine, fluorine, cyano, nitro, hydroxy, methyl,difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, ethynyl, 3,3,3-trifluoroprop-1-yn-1-yl or cyclopropyl,R⁸ represents hydrogen, chlorine or fluorine, R² represents hydrogen,bromine, chlorine, fluorine, cyano, C₁-C₃-alkyl, difluoromethyl,trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, C₁-C₃-alkoxy, difluoromethoxy, trifluoromethoxy,1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,methylcarbonyl or cyclopropyl, R³ represents hydrogen, C₁-C₅-alkyl,C₁-C₄-alkoxy, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,1,1,2,2,2-pentadeuteroethyl, 3,3,3-trifluoro-2-hydroxyprop-1-yl,3,3,3-trifluoro-2-methoxyprop-1-yl, 3,3,3-trifluoro-2-ethoxyprop-1-yl,prop-2-yn-1-yl, cyclopropyloxy or cyclobutyloxy, where alkyl may besubstituted by a substituent selected from the group consisting offluorine, cyano, hydroxy, difluoromethyl, trifluoromethyl, methoxy,ethoxy, difluoromethoxy, trifluoromethoxy, C₃-C₆-cycloalkyl, 4- to6-membered oxoheterocyclyl, 4- to 6-membered thioheterocyclyl,1,4-dioxanyl, phenyl and pyridyl, where cycloalkyl may be substituted by1 to 2 substituents independently of one another selected from the groupconsisting of fluorine, hydroxy, methyl, ethyl, methoxy, ethoxy,difluoromethyl, trifluoromethyl, difluoromethoxy and trifluoromethoxy,and where oxoheterocyclyl and thioheterocyclyl may be substituted by 1to 2 substituents independently of one another selected from the groupconsisting of oxo, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, R⁴ represents hydrogen, R⁵ represents a group of theformula

where # is the point of attachment to the nitrogen atom, R⁹ representshydroxycarbonyl or 5-membered heterocyclyl, where heterocyclyl may besubstituted by 1 to 2 substituents independently of one another selectedfrom the group consisting of oxo, hydroxy, thioxo, sulphanyl, methyl,difluoromethyl, trifluoromethyl,2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl and2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl, where methyl may besubstituted by a methoxy substituent, R¹⁰ represents hydrogen, chlorine,fluorine or methyl, R¹¹ and R¹² together with the carbon atoms to whichthey are attached form a 5-membered heterocycle, where the heterocyclemay be substituted by 1 to 2 substituents independently of one anotherselected from the group consisting of oxo, chlorine, hydroxy,hydroxycarbonyl, methyl, difluoromethyl, trifluoromethyl,1,1,2,2,2-pentafluoroethyl, 2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyland 2-methoxycarbonyl-1,1,2,2-tetrafluoroethyl, R¹³ represents hydrogen,chlorine, fluorine, methyl or methoxy, or a salt thereof, solvatethereof or solvate of a salt thereof.
 2. The compound of claim 1,wherein R¹ represents a group of the formula

where * is the point of attachment to the oxopyridine ring, R⁶represents chlorine, R⁷ represents bromine, chlorine, cyano, nitro,methyl, difluoromethyl, trifluoromethyl, difluoromethoxy,trifluoromethoxy, ethynyl or cyclopropyl, R⁸ represents hydrogen, R²represents hydrogen, chlorine, fluorine, cyano, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, isopropoxy,difluoromethoxy or 2,2,2-trifluoroethoxy, R³ represents hydrogen,C₁-C₅-alkyl, ethoxy, 1,1,2,2,2-pentadeuteroethyl or prop-2-yn-1-yl,where C₁-alkyl may be substituted by a substituent selected from thegroup consisting of difluoromethyl, trifluoromethyl, cyclopropyl,cyclobutyl, cyclohexyl, oxetanyl, tetrahydrofuranyl,tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, 1,4-dioxanyl, phenyland pyridyl, where cyclopropyl, cyclobutyl, cyclohexyl and oxetanyl maybe substituted by 1 to 2 substituents independently of one anotherselected from the group consisting of fluorine, hydroxy, methyl, ethyl,methoxy and trifluoromethyl, and where tetrahydrofuranyl,tetrahydro-2H-pyranyl and tetrahydro-2H-thiopyranyl may be substitutedby 1 to 2 substituents independently of one another selected from thegroup consisting of oxo, methyl and ethyl, and where C₂-C₄-alkyl may besubstituted by a substituent selected from the group consisting offluorine, hydroxy, trifluoromethyl, methoxy and trifluoromethoxy, R⁴represents hydrogen, R⁵ represents a group of the formula

where # is the point of attachment to the nitrogen atom, R⁹ representshydroxycarbonyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl or dihydrooxazolyl, where oxazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, triazolyl anddihydrooxazolyl may be substituted by 1 to 2 substituents independentlyof one another selected from the group consisting of oxo, hydroxy,thioxo, sulphanyl, methyl, trifluoromethyl and2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl, where methyl may besubstituted by a methoxy substituent, R¹⁰ represents hydrogen, chlorine,fluorine or methyl, or R⁵ represents 2,3-dihydro-1H-indazol-6-yl,1H-benzimidazol-6-yl, indol-6-yl, 2,3-dihydro-1H-indazol-5-yl,2,3-dihydro-1H-benzimidazol-5-yl, indol-5-yl, 1H-indazol-6-yl or1H-indazol-5-yl, where the 5-membered heterocycle in2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl,2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl,indol-5-yl, 1H-indazol-6-yl and 1H-indazol-5-yl may be substituted by 1to 2 substituents independently of one another selected from the groupconsisting of oxo, chlorine, hydroxycarbonyl, methyl andtrifluoromethyl, and where the benzyl ring in2,3-dihydro-1H-indazol-6-yl, 1H-benzimidazol-6-yl, indol-6-yl,2,3-dihydro-1H-indazol-5-yl, 2,3-dihydro-1H-benzimidazol-5-yl,indol-5-yl, 1H-indazol-6-yl and 1H-indazol-5-yl may be substituted by asubstituent selected from the group consisting of fluorine and methoxy,or a salt thereof, solvate thereof or solvate of a salt thereof.
 3. Thecompound of claim 1, wherein R¹ represents a group of the formula

where * is the point of attachment to the oxopyridine ring, R⁶represents chlorine, R⁷ represents cyano or difluoromethoxy, R⁸represents hydrogen, R² represents chlorine, cyano, methoxy, ethoxy ordifluoromethoxy, R³ represents methyl, ethyl, n-propyl,2-methylprop-1-yl or n-butyl, where methyl may be substituted by asubstituent selected from the group consisting of difluoromethyl,trifluoromethyl, cyclopropyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl,tetrahydro-2H-pyranyl, 1,4-dioxanyl, phenyl and pyridyl, wherecyclopropyl, cyclobutyl and cyclohexyl may be substituted by 1 to 2substituents independently of one another selected from the groupconsisting of fluorine, hydroxy, methyl, methoxy and trifluoromethyl,and where ethyl, n-propyl and n-butyl may be substituted by asubstituent selected from the group consisting of fluorine, methoxy andtrifluoromethoxy, R⁴ represents hydrogen, R⁵ represents a group of theformula

where # is the point of attachment to the nitrogen atom, R⁹ representshydroxycarbonyl, oxadiazolyl, pyrazolyl, triazolyl or tetrazolyl, whereoxadiazolyl and pyrazolyl may be substituted by 1 to 2 substituentsindependently of one another selected from the group consisting of oxo,hydroxy and trifluoromethyl, and where triazolyl may be substituted by asubstituent selected from the group consisting of trifluoromethyl and2-hydroxycarbonyl-1,1,2,2-tetrafluoroethyl, R¹⁰ represents hydrogen orfluorine, or R⁵ represents 2,3-dihydro-1H-indazol-6-yl,1H-benzimidazol-6-yl, 2,3-dihydro-1H-benzimidazol-5-yl or1H-indazol-5-yl, where the 5-membered heterocycle in2,3-dihydro-1H-indazol-6-yl may be substituted by 1 to 2 substituentsindependently of one another selected from the group consisting of oxoand methyl, and where the benzyl ring in 2,3-dihydro-1H-indazol-6-yl maybe substituted by a fluorine substituent, and where the 5-memberedheterocycle in 1H-benzimidazol-6-yl may be substituted by ahydroxycarbonyl substituent, and where the 5-membered heterocycle in2,3-dihydro-1H-benzimidazol-5-yl may be substituted by an oxosubstituent, and where the 5-membered heterocycle in 1H-indazol-5-yl maybe substituted by a chlorine substituent, or a salt thereof, solvatethereof or solvate of a salt thereof.
 4. A process for preparing acompound of formula (I) or a salt thereof, solvate thereof or solvate ofa salt thereof according to claim 1, comprising [A] reacting a compoundof the formula

in which R¹, R², R³, R⁴ and R¹⁰ have the meaning given in claim 1, andR¹⁴ represents tert-butyl, with an acid to give a compound of theformula

in which R¹, R², R³, R⁴ and R¹⁰ have the meaning given in claim 1, andR⁹ represents hydroxycarbonyl, or [B] reacting a compound of the formula

in which R¹, R², R³, R⁴ and R¹⁰ have the meaning given in claim 1, andR¹⁴ represents methyl or ethyl, with a base to give a compound of theformula

in which R¹, R², R³, R⁴ and R¹⁰ have the meaning given in claim 1, andR⁹ represents hydroxycarbonyl, or [C] reacting a compound of the formula

in which R¹, R² and R³ have the meaning given in claim 1, with acompound of the formula

in which R⁴ and R⁵ have the meaning given in claim 1, in the presence ofa dehydrating agent to give a compound of the formula (I), or [D]reacting a compound of the formula

in which R², R³, R⁴ and R⁵ have the meaning given in claim 1, and X¹represents chlorine, bromine or iodine, with a compound of the formulaR¹-Q  (VI), in which R¹ has the meaning given in claim 1, and Qrepresents —B(OH)₂, a boronic ester, or radical —BF₃ ⁻K⁺, under Suzukicoupling conditions to give a compound of the formula (I).
 5. Theprocess of claim 4, wherein the boronic ester is boronic acid pinacolester.
 6. A pharmaceutical composition comprising a compound accordingto claim 1 and an inert, nontoxic, pharmaceutically suitable excipient.7. A method for the treatment of a thrombotic or thromboembolic disordercomprising administering a therapeutically effective amount of at leastone compound of claim 1 to a human or animal in need thereof.
 8. Amethod for the treatment of an ophthalmic disorder comprisingadministering a therapeutically effective amount of at least onecompound of claim 1 to a human or animal in need thereof.